The Reds lingering hopes of a top four finish were mathematically ended at White Hart Lane on Sunday, leaving next week's European final in Stockholm against Ajax as the overriding priority.
United claimed the season's first piece of major silverware with EFL Cup triumph at the expense of Saints, who sit comfortably in mid table and still with a chance of a top eight finish in Claude Puel's debut campaign at the helm.
Victory at relegated Middlesbrough last time out ended a run of five games without a win and saw the Saints wedged between West Brom and local south coast rivals Bournemouth.
United are likely to be much changed again for this twice rearranged midweek fixture.
Paul Pogba will miss out following the death of his father, but Marouane Fellaini is available again having completed his three-match domestic ban.
Chris Smalling, Phil Jones, Juan Mata and Anthony Martial all look set to feature but Daley Blind will be rested, with youngsters Axel Tuanzebe, Demi Mitchell and Scott McTominay also pushing for inclusion.
Saints will certainly be pleased to see Zlatan Ibrahimovic absent from the team sheet - the Swede having hit four in the two league and cup encounters between the sides so far including the match-winning brace at Wembley.
Southampton duo Virgil van Dijk and Alex McCarthy will not feature despite returning to training this week, but Charlie Austin could push for a place up front after six months out.
United manager Jose Mourinho said: "I have to build some players with the minimum of conditions to fight for a result.
"We always want to fight - I don't want to field a team where people think we aren't going fighting for a result because we always are.
"Now it is time to finish with two good league games to close the Premier League and reach the Europa League final with momentum and in the best shape we can.
"What I want from the players is a positive attitude, good team spirit and an understanding of the current situation of rotating players to keep them fresh.
"I'm trying to get people to be the best that they can, against Southampton I will give two or three players a rest, and against Crystal Palace another two or three more - to try to arrive in the final in the best possible condition."
Form guide: Southampton L L D D L W United D D W L D L
Match odds: Southampton 8/5 Draw 12/5 United 7/4
Referee: Mike Dean (Wirral)
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