United make the long trip to the south coast with little to play for, but Jose Mourinho must ensure that his players do not take their foot off the gas ahead of next week's Europa League final with Ajax.
After finishing no lower than eighth position over the past three seasons, Southampton supporters were justified in expecting a similar showing in Claude Puel's first year at the club, but while they still have an opportunity to extend that period to four years, they will not have earned it in the fashion that they would have hoped for.
A best-case scenario for Southampton is 51 points - five fewer than their worst effort since 2013-14 - and it is that figure which Puel is likely to be judged on when the club's owners assess the team's performance since August.
Reports have suggested that there is discontent among the first-team squad, with some players not supportive of Puel's playing style or simply wanting to move on to pastures new, but regardless of the reasons, they still have a job to do over the final two fixtures.
On Sunday, Puel will expect to get the better of a struggling Stoke City side but he will be aware that recording a win over a United side who have still only lost five times in the league this season would be a statement result that could help give him a second year with the Saints.
Puel has had to deal with the absence of Charlie Austin since December but after a brief cameo at Middlesbrough last weekend, he is in line to up his recovery and try to add to his return of six goals from 14 top-flight appearances.
More changes are expected after Puel rotated his team for the trip to the Riverside Stadium but with his side struggling for goals for the majority of the season, the return of the 27-year-old may prove significant.
Recent form: LLDDLW
From his team selection against Tottenham Hotspur, Mourinho made it clear that he was prioritising his team's participation in the Europa League final with Ajax on May 24, but while rest is necessary for many of his squad after a energy-sapping campaign, he must ensure that too much rotation does not lead to problems in Stockholm.
Many of the players picked for the game at White Hart Lane were still looking for match sharpness but the manner of the defeat - despite the 2-1 scoreline - may have concerned Mourinho because they were off the pace against one of their rivals.
The likelihood is that Mourinho will play a full-strength team for the trip to Southampton before making mass changes for the home clash with Crystal Palace at the weekend but while he will be wary of injuries, his team not playing at a high intensity may prove a disadvantage when they go toe-to-toe with a vibrant and energetic Ajax.
It will not be lost on Mourinho that United have only won once in their last half-a-dozen fixtures, with the success over Celta Vigo only coming as a result of a Marcus Rashford free kick, so there are issues to be solved even at this late stage of the campaign.
There are positives for the North-West outfit with both Anthony Martial and Wayne Rooney both showing some kind of form against Spurs, but the likes of Chris Smalling and Phil Jones still require games if they are to be seen as able deputies to Eric Bailly and Marcos Rojo.
United's result on Wednesday night will be largely considered irrelevant but unless Mourinho finds some answers to the selection dilemmas he faces ahead of the trip to Sweden, it will be argued that they may head into that game as underdogs if improvements are not made over the coming days.
Recent form: WWDDLL
Recent form (all competitions): DDWLDL
Puel is likely to ring the changes after making seven alterations for the trip to the North-East on Saturday.
Matt Targett is also in contention after not featuring since October because of a long-term injury.
Ander Herrera and Matteo Darmian could also feature further back, but Bailly is likely to drop to the bench with the defender expected to feature on Sunday due to his suspension from the Europa League final.
Southampton possible starting lineup:
Forster, Soares, Yoshida, Stephens, Bertrand, Romeu, Davis, Ward-Prowse, Redmond, Boufal, Gabbiadini
Manchester United possible starting lineup:
De Gea, Valencia, Smalling, Blind, Darmian, Herrera, Fellaini, Lingard, Mata, Mkhitaryan, Rashford,
Head To Head
Wednesday's contest represents the 122nd time in which these two clubs have faced each other in a competitive fixture, with United claiming 63 wins and Southampton only prevailing on 28 occasions.
However, despite the lopsided historical record, Southampton have won twice during the last half-a-dozen games, although both triumphs came at Old Trafford.
The Saints have not registered a win over United at their home ground since 2003 when James Beattie scored to secure a 1-0 win just two years after they had left The Dell.
We say: Southampton 1-1 Manchester United
It is difficult to assess how United will approach this match but given that Southampton have struggled of late, they should be strong enough to claim a point. The home side will see this as an opportunity to secure another top-10 finish, but they may have to wait until the final game.