The Red Devils are focused on the UEFA Europa League final against Ajax on May 24 and will not want to pick up any injuries on the south coast.
The Saints are safe in mid-table, but a victory against United could see them rise above West Bromwich Albion into eighth place.
Here is how you can watch the action:
Date: Wednesday, May 17
Time: 7:45 p.m. BST/2:45 p.m. ET
TV: Sky Sports 1 (UK only), NBC (U.S. only)
Team News and Preview
United manager Jose Mourinho has a chance to add a second trophy to the cabinet from his first term in charge at Old Trafford after February's EFL Cup win over these same Saints, but the Premier League campaign has been a failure.
The purchases of Zlatan Ibrahimovic and Paul Pogba were supposed to trigger a title challenge from the fallen Manchester giants, but United have laboured outside of the top four.
One of Mourinho's major selection choices is to decide who starts the Europa League final in goal, and it appears the Portuguese has opted for Sergio Romero. This should mean No. 1 David De Gea will face Southampton.
According to Jake Lambourne of The Sun, Mourinho has explained his goalkeeping decision.
The manager said:
"There's no dilemma, They are two fantastic goalkeepers.
"I think it is fair Sergio is going to play the final and David accepts. He accepts that because, especially, he has already played Europa League matches.
"I never saw in all my career two goalkeepers to be so friendly because it is a position when you always have a little bit of rivalry, especially if you are both the same kind of level.
"You are speaking about Argentina national goalkeeper and Spain national goalkeeper. They are friends and they support each other all the time. I never saw a bad face."
Matteo Darmian is expected to start as Daley Blind is rested ahead of the European final against his former club. Pogba missed the game at Tottenham Hotspur due to the death of his father, making his involvement at Southampton doubtful.
Saints boss Claude Puel is without injured goalkeeper Alex McCarthy and defender Virgil van Dijk, with full-back Sam McQueen unlikely to feature, per WhoScored. However, striker Charlie Austin is back from long-term injury and will be desperate for a start against the visitors.
After scoring just 41 goals in the league this season, Southampton will focus on improving this part of their game, having scored fewer goals than Swansea City, who are near the foot of the table.
The game is likely to be a drab affair considering United's commitments and the Saints' position as neither side will go for the jugular.
United's lack of interest in the match can only help the hosts as they seek their 13th league victory of the season, and Puel will want his side to take advantage of the unique situation.