With Manchester City already a point ahead with a game in hand, Ole Gunnar Solskjaer will have to conjure up a team good enough to get all three points off The Saints, who lie 11th on the log.
The Norwegian expects to have a full squad to choose from and could retain some starters who drew at Arsenal last week.
“Well apart from the wear and tear and, as you say, the quick turnaround, everyone should be available. They’re not injured anyway. It’s just a matter of energy levels and seeing how they feel tomorrow. There are no new, fresh injuries anyway,” Solskjaer told press.
Scott McTominay should be back after a stomach upset that saw him substituted prematurely against the Gunners, with Phil Jones the only remaining absentee through injury.
Anthony Martial could return in the centre-forward position ahead of talisman Edinson Cavani, with Marcus Rashford and Bruno Fernandes completing the attack.
Solskjaer is expected to maintain the same midfield that started against Arsenal, though Serbian Nemanja Matic could be preferred for his experience.
Predicted Manchester United XI: De Gea, Wan-Bissaka, Lindelof, Maguire, Shaw, McTominay, Fred, Pogba, Fernandes, Rashford, Martial
Southampton, on the other hand, will enter tonight’s contest off the back of a 1-0 home defeat to Aston Villa on Saturday.
Ralph Hasenhuttl’s men have failed to register a win since beating Liverpool at the start of January, losing each of their last three to Villa, Arsenal and Leicester, leaving them in 11th position on the log. The Saints have also not beaten Manchester United since January 2016.
They have only secured victory three times on the road this season but will be looking to take advantage of Man United’s stuttering home form.
Nathan Redmond could get a start on the wing after Theo Walcott picking up a problem against Villa, with Che Adams and Danny Ings expected up-front.
Predicted Southampton XI: McCarthy, Valery, Bednarek, Stephens, Bertrand, Redmond, Romeu, Ward-Prowse, Armstrong, Ings, Adams.