Jose Mourinho's side top the standings after one game, but their season has since been plunged into disarray and Valencia will be hopeful of taking advantage as they look to get off the mark in Europe this season.
Where to start? Everything seems to be going wrong for Manchester United at the moment, both on and off the pitch, and Tuesday's match could prove to be a pivotal one for the rest of their season.
With their hopes of a Premier League title challenge already seemingly in tatters, the Champions League represents the next biggest target in United's season, although fans will have seen little to convince them that they are capable of challenging Europe's elite just yet.
One thing is for sure - United must get their own house in order before they can start thinking of adding to their haul of silverware, with their season having spiralled into chaos and crisis since their opening match of Group H.
Things looked increasingly optimistic at that stage for Mourinho and co; United had recovered from back-to-back defeats by winning three games in a row across all competitions, and even Paul Pogba was making headlines for the right reasons as he put in a man-of-the-match display in a 3-0 win against Young Boys.
Pogba wore the armband for that match - something he will likely never do again under Mourinho - but his comments after the 1-1 draw with Wolverhampton Wanderers that weekend began the latest saga between player and manager which has undermined United's season more than anything else.
A penalty shootout defeat to Championship side Derby County saw them dumped out in the third round of the EFL Cup before they slumped to their third league loss of the season at West Ham United on Saturday, sealing their worst start to a campaign since 1989-90.
Such a dismal spell of form means that Mourinho's own future is beginning to make as many headlines as his fallout with Pogba, and it will not escape the attention of the masses if he falls to another defeat in the very tournament his proposed successor Zinedine Zidane has won three years in a row.
Even if Mourinho's relationship with Pogba is broken beyond repair, the only way to silence the rest of the dissonance around the club is to start winning matches. United have been beaten as many times as they have won this season, and on Tuesday could lose three successive games for the first time since September 2016.
As though Mourinho does not have enough problems on his plate, United also come into this match without a win at Old Trafford since the very opening day of the season - almost two months ago. Not since January 2014 have they lost successive home games and you have to go back to last century for their most recent run of four home games without a win.
There are reasons for optimism despite all of the doom and gloom surrounding the club at the moment, though; United have lost just one of their last 22 European matches at Old Trafford and have also only been beaten once in their last 18 home Champions League group games - winning eight of their last nine.
Continuing that run would be the perfect riposte to what has been a miserable 10 days for the club, although it would take a significant improvement from what we have seen from Mourinho's side during that time.
Recent Champions League form: W
Recent form (all competitions): WWWDLL
A lot has changed since Valencia's last visit to Old Trafford - when Sir Alex Ferguson's United were on their way to a third Champions League final in the space of four years - with the Spanish outfit also experiencing plenty of ups and downs in that time.
The 2018-19 campaign sees the two-time Champions League finalists return to European competition after two years away, having recorded back-to-back 12th-placed finishes in La Liga during which time they were at one stage managed by United legend Gary Neville.
Los Che returned to where most are more familiar with seeing them last season, but they have made a disappointing start to the current campaign in Spain.
Marcelino's side sit 14th in the table after seven games, having only picked up their first win of the season on Saturday when they ran out 1-0 winners over Real Sociedad courtesy of Kevin Gameiro's first goal for the club.
Even with that win, Valencia are already seven points worse off than at the same stage of last season, and their Champions League campaign also got off to a losing start as they were beaten 2-0 at home by Juventus - despite seeing Cristiano Ronaldo dismissed for the Italian outfit in the first half.
Valencia conceded two penalties and missed one of their own during the hour in which they enjoyed an extra man, squandering a golden opportunity to pull off an unexpected result against the group favourites.
A lack of quality in front of goal has cost Valencia on other occasions this season too, and they arrive at Old Trafford having scored just twice in their last five outings across all competitions.
The defeat to Juventus was their fourth successive reverse in the Champions League - already their worst ever run - and on Tuesday they will be looking to avoid becoming only the third Spanish team to lose five consecutive games in the competition.
Los Che appear to be fairly kind opposition for United with their current troubles, then, but by the same token Marcelino's side will rarely find a better chance to beat the Red Devils at Old Trafford, and that could make them a dangerous proposition on Tuesday.
Recent Champions League form: L
Recent form (all competitions): DDLDDW
Marcos Rojo is also sidelined for the home side, who must decide whether to stick with the 3-5-2 experiment which has backfired on a couple of occasions this season or revert to a 4-3-3.
Pogba was hooked with 20 minutes remaining against West Ham and his place in the team is in doubt despite his two-goal performance on matchday one.
Alexis Sanchez is another high-profile name around whom doubts will swirl after he was left out of the matchday squad entirely for the trip to the London Stadium, although the Chilean is expected to start.
Rodrigo Moreno - who already has an Old Trafford goal on his CV - will battle it out with Gameiro and Michy Batshuayi for a place up front, while former Arsenal duo Francis Coquelin and Gabriel Paulista will also be hopeful of starting back on English soil.
Man Utd possible starting lineup:
De Gea; Valencia, Smalling, Lindelof, Shaw; Pogba, Matic, Fred; Rashford, Lukaku, Sanchez
Valencia possible starting lineup:
Neto; Vezo, Gabriel, Diakhaby, Gaya; Soler, Parejo, Kondogbia, Guedes; Gameiro, Batshuayi
Head To Head
These two sides have met on eight previous occasions, with five of those - and four of the last five - ending in draws. United have won two of the remaining three, with Valencia winning once
The most recent encounter provided one of those stalemates as the two sides played out a 1-1 draw at Old Trafford in the 2010-11 group stages.
United have now won just two of their last 13 matches against Spanish clubs - including six defeats - while Valencia have only won three of their 17 away games against Premier League opposition.
We say: Man Utd 1-1 Valencia
United will still be the favourites heading into this match, but with so much negativity around the club at the moment it is difficult to see them making the most of their superior quality. Valencia are not in the best form themselves, but will fancy their chances of getting something from this game.