With a little over half an hour to play at the Emirates Stadium on Sunday, Tottenham were heading towards a famous victory on enemy territory after overcoming an early deficit to take the lead.
If losing to their neighbours in a heated derby was not hard enough to take on its own, defeat for Tottenham - their fourth of the season in the top flight - saw them slip below the Gunners to fifth place on goal difference.
Pochettino admitted after the match that his side were made to pay at the end of a gruelling week that had seen them face Chelsea and Inter Milan, games in which the Lilywhites came out on top in to stretch their perfect run to six matches.
In beating Chelsea and Inter, adding to previous victories over PSV Eindhoven, West Ham United, Huddersfield Town and Crystal Palace across three competitions, Tottenham got their campaign well and truly back on track following a difficult October spell.
It would be harsh to suggest that Pochettino's men are back to square one after seeing their momentum halted by Arsenal, but the Argentine coach will know that there is no room for any slip-ups against Southampton (18th), Leicester City (eighth) and Burnley (19th) in their next three league outings.
Tottenham have a busy December programme, with their meeting against Arsenal kicking off a run of 10 games up to and including the trip to Cardiff City on New Year's Day. During that run, the Lilywhites again lock horns with the Gunners for a place in the EFL Cup semi-final, as well as travelling to Barcelona knowing that defeat will likely bring their Champions League campaign to an end.
Three high-intensity games in a week may have proved too much for Pochettino's men, but now they have the perfect chance to get the ball rolling again as they welcome an out-of-sorts and managerless Southampton to Wembley Stadium.
Recent form in Premier League: WLWWWL
Recent form (all competitions): WWWWWL
Positives may have been clear to see in the four-goal draw with Man United on Saturday evening, but it came too late to keep Hughes in a job as Southampton finally pulled the trigger less than 48 hours later.
In getting the shove from the club he only joined eight months ago, former Stoke City boss Hughes becomes the first manager in Premier League history to be sacked twice in the same calendar year.
Southampton now make the trip to the English capital with first-team assistant coach Kelvin Davis in the dugout, which may remain the case for next weekend's huge six-pointer with fellow relegation battlers Cardiff, unless a new man can be persuaded to take over beforehand.
Either way, the Saints are in desperate need of a lift after going 12 games in all competitions since last tasting victory, stretching back to a 2-0 away win over Palace in September - their longest-such run since going 13 matches between May and October 1998.
The Saints had the perfect chance to lift themselves out of the dropzone on Saturday when racing into a two-goal lead against Man United, only to concede their 25th and 26th goals of the season before the first half was over.
A draw was still a positive return on the whole, but it leaves Southampton a point adrift of safety ahead of games against Tottenham, Arsenal, Manchester City and Chelsea in four of their next seven matches. The new manager, whoever he may be, will likely need some time to get going.
Southampton have now dropped 33 points from winning positions since the start of last season - at least seven more than any other side - and their current tally of nine points is their worst-ever return at this stage of a Premier League campaign.
Davis can take some positives from what he saw in the United game, however, as well as the battling display at Leicester in the EFL Cup last week. Hughes fielded fairly inexperienced sides for both of those matches, and it may well be a case that Davis sticks with some of the younger members of his squad to help in this push for survival.
Recent form in Premier League: DDLDLD
Recent form (all competitions): DLDLLD
Danny Rose returned from injury with a late cameo in the North London derby and is in line to make his first start in two months here, while Kieran Trippier is also closing in on a return on the opposite flank.
In terms of the visitors, Mario Lemina is out through suspension and a number of others are carrying injuries, with Shane Long, Matt Targett, Ryan Bertrand, Michael Obafemi and Danny Ings among those expected to miss out on inclusion.
Obafemi's absence is good news for Charlie Austin, who has not been used in Southampton's last two games, and Steven Davis should also benefit with a place in midfield.
Stuart Armstrong's form is a rare positive for the Saints, needing a goal against Tottenham in midweek to become the first player to net in three successive league matches for the south coast side since Manolo Gabbiadini in March 2017.
Tottenham Hotspur possible starting lineup:
Lloris; Aurier, Foyth, Alderweireld, Rose; Winks, Dier; Lucas, Alli, Son; Kane
Southampton possible starting lineup:
McCarthy; Stephens, Yoshida, Vestergaard; Valery, Hojbjerg, Davis, Soares; Armstrong, Gabbiadini; Austin
Head To Head
Tottenham have been victorious in eight of their last 10 home matches against Southampton, losing in September 2003 and May 2016.
Since returning to the top tier of English football six years ago, the Saints have won one of their 12 league meetings with Spurs, losing nine of those.
The Lilywhites have also had three different hat-trick scorers in the Premier League against Southampton - Steffen Iversen, Jermain Defoe and Kane. Only Arsenal vs. Leicester and Man United vs. Newcastle United (four each) can boast more against a single opponent.
We say: Tottenham Hotspur 2-0 Southampton
Southampton have collected just five points from the last 30 on offer and are without a manager for this tough test. Tottenham may have suffered a hard-to-take defeat against rivals Arsenal in their most recent outing, meanwhile, but they have otherwise been in fine form over the past five weeks and should respond by taking all three points here.