Felipe Anderson's maiden strike for the Hammers put them ahead inside six minutes, and an own goal from Victor Lindelof doubled the home side's lead before the break.
Substitute Marcus Rashford pulled one back for the Red Devils on 71 minutes with a skilful near-post flick but United's comeback was nipped in the bud within three minutes.
Mark Noble's through-ball released Marko Arnautovic to finish past David de Gea for his fourth goal of the season, ensuring that United would have their lowest points total after seven games of a Premier League campaign.
Relive how the action unfolded with Sports Mole's minute-by-minute updates from the capital.
11.30amA home draw to Wolves, elimination to a Championship side in the EFL Cup and a civil war forming in camp; Manchester United are on the brink of a crisis. Can the Red Devils redeem themselves today or will West Ham United pile on the misery? Team news from the early kickoff at the London Stadium is coming up...
11.36amThe headline name in those two lineups is that of Paul Pogba, who is reportedly at loggerheads with Jose Mourinho but keeps his place in United's starting XI. Alexis Sanchez and Jesse Lingard are both missing from the squad entirely so Anthony Martial gets a chance to make an impression in attack.
11.38amThe Mirror has got into the Ryder Cup spirit by pairing up the Mourinho loyalists and the Pogba rebels. It claims that Martial, Luke Shaw, Eric Bailly and Phil Jones are also fed up with their manager's public criticism. Antonio Valencia, Nemanja Matic, Ashley Young, Marouane Fellaini and Sanchez are said to be siding with the boss. Three from each of those supposed camps make today's team for the Red Devils.
11.40amValencia is another mystery absentee from the United squad so Ashley Young takes the captain's armband and his place at right. Victor Lindelof and Chris Smalling get another opportunity to fine tune their defensive partnership and Matic is back from suspension to shield the back four.
11.42amMarcus Rashford has also served his ban to take his place on the bench, a start alluding him despite what we can assume to be injuries to both Sanchez and Lingard. Fred, after opening his account for United in the 1-1 draw with Wolves, is also a substitute as Mourinho puts his faith in Scott McTominay.
11.44amThe Hammers welcome back talisman Marko Arnautovic in the only change from last weekend's 0-0 draw with Chelsea. Andriy Yarmolenko and Felipe Anderson, summer signings who are starting to find their feet in England, return to flank the Austrian as Michail Antonio drops to the bench.
11.46amPromising youngster Declan Rice continues in a holding midfield role alongside the experience of Mark Noble and Pedro Obiang. Jack Wilshere is still sidelined but the Hammers have actually had a better balance in the centre of the park since Manuel Pellegrini introduced some extra legs.
11.48amWhile United were enduring a week of turmoil, West Ham were recording their biggest win in 35 years in thrashing Macclesfield 8-0. Academy graduate Grady Diangana stole the show with a second-half brace and has earned himself a place on the bench today ahead of more senior figures.
11.50amThere were also some pleasing contributions from Pellegrini's senior men in Wednesday's EFL Cup success. Robert Snodgrass bagged his first goals for the club since joining in January 2017 and Antonio broke a six-month drought. Aaron Cresswell - out of today's squad - did not do enough to impress though.
11.52amAntonio finds himself back on the bench today with Arnautovic fit again, but the 28-year-old forward will be a real asset to Pellegrini if he can rediscover his form from a season or two ago. He averaged a goal every 3.2 games across the 2015-16 and 16-17 campaigns.
11.54amWest Ham's attack have been pretty reliant on Arnautovic of late, with the Austrian having been directly involved in half of the club's last 40 league goals, scoring 14 and setting up six. That includes three goals and an assist since the start of this season.
11.56amThe Hammers have won just two of their eight top-flight games without Arnautovic since the Austrian joined from Stoke City last summer, and not since last September when they knocked off Huddersfield and Swansea. So it should come as little surprise that Pellegrini rushes him back in this afternoon.
11.58amWhile the Londoners are unbeaten since the international break, their home form needs turning around if they are to climb from 17th, following one point and a single goal from three matches. Today they are at risk of equalling the club's top-flight record of failing to score in three straight home games.
12.00pmIt has also been 358 minutes since the Hammers scored a Premier League goal against United, back in November 2016 when Diafra Sakho bagged at Old Trafford in a 1-1 draw. There are only two survivors in the West Ham team from that day - Obiang and Noble.
12.02pmWest Ham have not failed to win any of their opening four Premier League home games of a season since 2009, when it took them until November to taste victory on their own soil. Six more home wins did follow that campaign as they avoided relegation by just five points.
12.04pmThe Hammers' biggest London Stadium scalp of last season was against Chelsea when Arnautovic - who else - scored the only goal in a 1-0 derby win. However, that is the only triumph in their past 16 league encounters with the division's established top-six teams.
12.06pmDefeat this afternoon for United would equal their worst return of 10 points after seven matches of a Premier League season. It could also leave them as far as 11 points adrift of the top of the table by the close of play - at the same point last term they were joint top.
12.08pmThe Red Devils have kept one clean sheet in the Premier League this season, conceding nine times in six games. That is their worst defensive record at this stage of the campaign in four years, and will be a huge point of frustration for Mourinho after the board's failure to land his centre-back targets in the transfer window.
12.10pmRomelu Lukaku marked United's last away match with his 20th Premier League goal for the club - the 24th player to reach that milestone. Today the Belgian could become the first to score in their opening four away matches of a Premier League season.
12.12pmWest Ham have been Lukaku's most frequent victims in English football, with the 25-year-old having found the net 11 times in as many matches with the Iron. Martial also has a good record against West Ham - six goals and two assists in his last five appearances which may be why he got the nod today.
12.14pmUnited have won only four of their last 15 top-flight fixtures in London, losing eight of those. Struggling in the capital must be an alien feeling to Mourinho after he oversaw a run of 77 unbeaten league matches over the course of his two spells at Chelsea.
12.16pmPellegrini and Mourinho are familiar enemies having faced each other as managers 13 times previously across their time in England and Spain. The Portuguese has bested the Chilean on seven occasions, with three wins for Pellegrini.
12.18pmIt has been a tetchy rivalry that started when the Special One bulldozed into Real Madrid as Pellegrini's replacement and slyly misnamed the South American as 'Pellegrino', a mistake that he has purposefully repeated since. Pellegrini later retorted that Mourinho's sides play "like a small team, like Stoke"
12.20pmPellegrini took the opportunity to reignite the war of words this week by questioning the unrest at Old Trafford. The Daily Mail quotes him as saying: "Maybe big names are not so hard to manage," referencing the Pogba situation.
"But, of course, they are young and everyone has a different character and the manager must try to reach the best way to have his commitment to your project, and every manager has a different way."
12.22pmThe West Ham boss may have reason to be concerned over one of his own midfielders with Declan Rice having reportedly turned down a new contract. The 19-year-old has caught the eye as a deep-lying midfielder in recent weeks and would be a free agent at the end of next season.
12.24pmJust over five minutes until kickoff at the London Stadium, where the sun is shining. Can that part the dark clouds that are hanging over Mourinho and his increasingly fragile Red Devils' reign?
12.26pmHEAD-TO-HEAD: West Ham's solitary victory in 19 Premier League games against United came in May 2016, a 3-2 victory in their last ever game at Upton Park. They have lost 13 of the previous 18 although did hold the Red Devils to a 0-0 draw in this fixture last season.
12.28pmPREDICTION: The Hammers are coming into some form and have the pace and trickery up front to cause this shaky United defence problems. Mourinho will be demanding a response to last week's setbacks and I expect him to get one - if he doesn't it would be a strong indictment of where the dressing room sits. I will go 2-1 United, but if the likes of Pogba and Martial don't turn up then it could be another humbling day for the visitors.
1 minKICKOFF: The action is underway in front of 60,000 fans who have got this wonderful venue rocking for the first whistle. Michael Oliver - one of the Premier League's most senior officials - is today's referee.
2 minYarmolenko earns West Ham an early corner and Balbuena gets above Smalling to win his header, but he can't direct it goalwards. The Paraguayan has already become a fixture in this Hammers team.
4 minThe hosts have made a confident start, seeing a lot of the ball in the United half. That has allowed us to see the shape Mourinho has gone with today, and it looks like wing backs, with McTominay in the defensive three and Young and Shaw on the flanks.
6 minGOAL!GOAL! WEST HAM 1-0 MAN UTD (FELIPE ANDERSON)
6 minIt is the worst possible start for United and Mourinho with West Ham going ahead with barely more than five minutes on the clock. Noble plays a nice pass inside Shaw to release Zabaleta to the byline and he squares for Anderson to stylishly flick the ball beyond David de Gea from a few yards out. Zabaleta was borderline offside but Lindelof may have been playing him on in the middle.
8 minAlready Zabaleta is proving a terrific outlet for the Hammers with this reshaped United team not sure who should be picking up the runs of the full-back. Shaw has not got much defensive support and Yarmolenko and Zabaleta are outnumbering the England international on every attack.
10 minWe get the first glimpse of Pogba as he turns a pass into the feet of Lukaku but a heavy first touch from the Belgian gifts West Ham the ball back. Noble spreads it to Anderson and only the offside flag going up against Yarmolenko prevents the hosts from getting another cross in from the right.
12 minUnited's own right-back gets forward now with Young delivering into a superb area for Lukaku and Martial to attack. Both are offside though, which means that Martial's poor execution of a header across goal will not be so heavily scrutinised. That would have been a poor miss had the flag stayed down.
14 minMartial makes a decent run into the right channel but gets his feet in a mess and dribbles the ball behind for a goal kick.
16 minThe visitors are showing signs of settling into the match now and are having some good moments down their right flank. They may feel that they can target Masuaku, whose strength is not defending. Anderson is neglecting to track back so United have the numbers, much like West Ham do on their right.
18 minNoble knocks a ball over the top for Arnautovic but Smalling does just enough to block the run of the Austrian, allowing De Gea to come off his line and collect, albeit at the second attempt.
20 minDiop brings a powerful Lukaku run in off the right flank to a halt with a perfectly-timed slide challenge.
20 minDiop brings a powerful Lukaku run in off the right flank to a halt with a perfectly-timed slide challenge. He is then well positioned at the near post to turn away a Young cross, and Lukaku is offside from the follow-up delivery.
22 minOFF THE POST! Good move from United, with McTominay stepping up from the back to release Young with a delightful through-pass. The wing-back deliverys to the near post where Lukaku gets across the defender to head against the outside of the woodwork.
24 minShaw makes a mess of what could have been a useful Fellaini knockdown by dragging his first-time cross horribly behind the United bodies in the box. With this system, Fellaini will have more freedom to get in the box than previous weeks and we know he can be a massive nuisance in there.
26 minPogba attempts to turn a first-time pass around the corner for Lukaku but hits it straight out for a goal kick.
28 minAfter West Ham's bright start, United have enjoyed the better of the last 10 minutes but seem to be a bit one-dimensional going forward at the moment, using Young down the right wing. Surely in a midfield three, with a back three behind them, there would be room for the creativity of Juan Mata?
30 minThis has a lot to do with what is going on in front of him, but De Gea has dipped in form himself after a difficult World Cup...
32 minPatient build-up play from West Ham as they switch it from left to right. Noble knocks a decent ball into the box for Arnautovic to flick on, but Smalling follows the run and heads behind himself.
34 minThe corner eventually comes to Yarmolenko who gets away a snap-shot 15 yards out which is blocked by Lindelof.
36 minPogba is tackled and then outmuscled by Zabaleta and concedes a free kick in his attempt to win the ball back.
38 minThe Frenchman is not having a great game so far but is continuing to show for the ball. A sharp turn on the edge of the box tees him up for a shot which is deflected behind for the first of a succession of corners, which come to nothing. McTominay did want a penalty following a collision with Masuaku but didn't have a case.
40 minAfter messing up a short free-kick routine, Anderson pounces on the loose ball to skip past Shaw and deliver an excellent cross to the far post, where Lindelof was on hand to clear under little pressure.
42 minIt looks as though Martial has turned away from Balbuena on the halfway line but the South American recovers to make a great tackle and launch a Hammers breakaway which nearly yields a chance for Arnautovic.
43 minGOAL!WEST HAM 2-0 MAN UTD (ANDRIY YARMOLENKO)
43 minThings go from bad to worse for United, although on this occasion they can count themselves very unlucky. A corner is only cleared as far as Yarmolenko who eventually works some space to get a shot away on his left foot, and it takes a massive deflection to take it into the opposite corner from where it was originally heading. That may well go down as a Lindelof own goal but the Swede is blameless.
45 minMourinho tried something different with this system but now he needs to have a rethink at half time. Because if United cannot turn things around then serious questions are going to be asked about some of the tactics and team selection that the Portuguese has gone with this afternoon.
1.22pmThe half-time whistle is greeted by thunderous cheers by the West Ham fans who have just seen their team completely outplay Manchester United in the opening 45 minutes. Goals from Felipe Anderson and Andriy Yarmolenko give them a 2-0 lead. A penny for Mourinho's thoughts at half time?
1.24pmThis 3-5-2 shape simply has not worked for United. McTominay looks alien to his role in the three-man defence, and that is because he is. What does it say about Mourinho's opinion of Eric Bailly that the Red Devils manager would rather use an untried midfielder there than a senior centre-back?
1.26pmAlthough few United fans would argue with dropping Sanchez and Lingard, who have gone over 2,000 minutes between them without a Premier League goal, Mourinho has got the attacking balance wrong. United have too many defensive-minded players and can't get far enough up the pitch.
1.28pmLet's address what Mourinho undoubtedly will in his post-match interview if things stay the same come full time. Pablo Zabaleta was perhaps marginally offside for the opening goal and Yarmolenko's strike for the second was heading off target before the deflection. Nevertheless, United have been poor and have only created one chance of their own - when Romelu Lukaku headed against the post. No shots on target at all.
1.30pmSTAT: The Red Devils have not come from behind to win at West Ham since Sir Alex Ferguson's title-winning season of 2010-11.
46 minKICKOFF: The action resumes and so far there is no changes from Mourinho. There needs to be a change in attitude and application from his players though otherwise the back pages tomorrow write themselves...
48 minAnderson nearly drops a free kick over the United back-line but Matic stretches to make a clearing header. The ball is recycled to Noble whose weak shot is comfortably held by De Gea.
50 minLindelof spreads the play nicely to Shaw in an advanced position down the left but the cross from the full-back is poor.
52 minShocking stuff from United, whose training-ground corner routine is cut short on the edge of the box by Noble who starts a West Ham counter. The ball is eventually switched to Arnautovic, but he can't bring Anderson's pass under control and the volley that follows is high and wide.
54 minFellaini brings down Young's throw-in on his chest and spins easily away from Rice, firing a volley across the box but it was neither a cross nor shot and it flies behind for a goal kick. Lazy defending from Rice though.
56 minStrong defending from Smallng who holds up Arnautovic and times his tackle superbly as the Austrian looked to turn and get a shot away.
57 minSUBSTITUTION: Mourinho has seen enough of this 3-5-2 and dumps Lindelof to bring on Rashford. That means McTominay in a back four now - another vote of no confidence in one of his recognised defenders. It is 4-2-3-1 with Fellaini behind Lukaku, and Martial and Rashford out wide.
59 minMartial has only been on the left wing for a couple of minutes and already produced some magic, weaving his way through two defenders in the tightest of spaces by the byline and winning United a corner. Over on the right, Rashford whips in a cross which is easy pickings for Lukasz Fabianski.
61 minA promising situation for United goes begging as Young is penalised for handball in the process of bringing the ball down on his way into the box. Mourinho does seem to have taken off the handbrake here.
63 minArnautovic has stayed down following a tackle from Smalling and Noble knocks the ball out of play so he can receive treatment.
65 minSAVE! Fabianski has not had a save to make today until now, and boy is it a good one. Young's delivery is right onto the head of Fellaini who powers an effort towards goal. Fabianski's whole body is behind the line but he somehow gets down to claw the ball away. Referee Oliver looks at his watch...nothing!
67 minNoble is having an excellent game. He can be an easy target when West Ham don't play well but his use of the ball today has been flawless.
68 minCLOSE! An opportunity for the Hammers to wrap things up but Anderson overhits his pass to Arnautovic who would have been through one-on-one.
70 minSUBSTITUTION: This will keep the rumour mill swirling - Pogba is off, and so is Martial as Mourinho turns to Mata and Fred in an attempt to rescue something from this game. In fairness, the Frenchman had not played well and just misplaced two passes in a row.
71 minGOAL!WEST HAM 2-1 MAN UTD (MARCUS RASHFORD):
71 minOut of nowhere, United have a route back into the game. It is a delightful finish from Rashford who attacks the front stick from a corner and connects exquisitely with a back-heel flick which catches Fabianski off guard and sneaks in at the near post.
74 minGOAL!WEST HAM 3-1 MAN UTD (MARKO ARNAUTOVIC)
74 minThe United comeback lasts all of three minutes as Arnautovic quickly restores West Ham's two-goal lead. Noble picks out his run with a simple through-ball through the heart of the visiting defence, and the Austrian keeps his cool to bury his fourth goal of the season past De Gea. So, so easy for the Hammers.
76 minSUBSTITUTION: West Ham's attack were looking a little leggy before that third goal and Yarmolenko has been withdrawn in favour of Robert Snodgrass, who continues his record of playing in every game this season, having spent last season out in the wilderness.
78 minYELLOW CARD! The first yellow card of the game is shown to Young, who hacked down Anderson during a spell of West Ham keep-ball which had prompted shouts of 'Ole' from the home fans. The United contingent won't mind that from their captain for the day - a tackle which displays some passion and determination.
80 minShaw goes direct to Fellaini who forces Masuaku to clear behind for a corner. The delivery from Mata is long and recycled by Lukaku, whose return ball into the box is claimed by Fabianski.
82 minSHOT! McTominay tries his luck from 25 yards out and really gets hold of his shot which Fabianski pushes away.
84 minSUBSTITUTION: Arnautovic gets a standing ovation from the home fans as he comes off for Antonio.
86 minFabianski has really stood up tall in the last 10 minutes, taking every cross cleanly to help the hosts wind the clock down.
88 minWe are approaching Fergie time here, but this United team does not have a fraction of the fear factor that its predecessors did. They have not created a clear-cut chance since West Ham's third goal and a late comeback here looks incredibly unlikely.
90+1 minIn the first of four minutes of stoppage time, Antonio wriggles through Young and tries to catch De Gea out with a chip from an impossible angle, but the Spaniard was never going to be beaten from there.
90+3 minSUBSTITUTION: A fine afternoon for West Ham is capped with a Premier League debut for midweek hero Grady Diangana, who replaces Felipe Anderson for the final few minutes here.
2.26pmA third poor result in a week for United, and they can have no complaints. Mourinho got his tactics wrong and his players did not have an answer to West Ham's new-found swagger. This is now their worst return of 10 points after seven matches of a Premier League season. Is the writing on the wall for Jose?
2.28pmThat's it from our coverage from the London Stadium. You can read our report on the action here. Stay with Sports Mole for coverage from across the Premier League this afternoon including Arsenal vs. Watford and Man City vs. Brighton. Thanks for joining me for this one. Goodbye!