Ralph Hasenhuttl's side goes into the fixture at St.Mary's in fifth place, with the Red Devils five places down the table in tenth - but having won their last three games in all competitions.
Danny Ings will once again be absent from Southampton's squad due to a knee injury which required an operation. Saints have proved doubters wrong in maintaining their impressive start without their star man, although he is on course to return in early December.
Along with Ings, Nathan Redmond will also be sidelined for this fixture with a hamstring injury but is expected to return for their South Coast clash against Brighton on the following weekend. While Mohammed Salisu is expected to miss out once more but said to be making great progress.
Hasenhuttl will be boosted by the return of Jake Voskins following a knee injury, but he has turned out for the under-23's last Sunday and looks set to return to the side.
Manchester United, on the other hand, will be without Phil Jones and Luke Shaw with respective knee and hamstring injuries. While Jese Lingard will once again be sidelined due to a case of Coronavirus.
Ole Gunnar Solskjaer will be boosted with the expected return of Paul Pogba, who is expected to return to the squad following an ankle injury.
Eric Bailly could also very much be back in contention to should the Ivorian recover from his muscle injury in time.
Southampton (possible 4-4-2) McCarthy, Walker-Peters, Vestergaard, Bednarek, Armstrong, Ward-Prowse, Romeu, Djenepo, Adams, Walcott
Manchester United (possible 4-2-3-1) de Gea, Wan Bissaka, Lindelof, Maguire, Telles, McTominay, Matic, Greenwood, Fernandes, Rashford, Martial
The home side are undoubtedly in some of the best form in their recent history and with a win on Sunday could go top once more - providing other results go their way.
Southampton haven't lost since September 20th, against Tottenham, and since then have won five from seven, with two draws against Chelsea and Wolves. The stalemate coming against Wolves last weekend as Theo Walcott scored in a 1-1 draw.
Ones to watch
In the absence of Danny Ings, Che Adams has really stepped up and been a real threat for the South Coast side, despite only scoring on three occasions he has created plenty going forward and will keep the Manchester United backline on their toes.
As will wideman Stuart Armstrong who has created many chances this season with his pace and trickery and one for the Red Devil's fullbacks to watch.
For their counterparts in this match, there is one main man to pick for Southampton to watch, with his six goals in eight league games, Bruno Fernandes is his sides real threat and has shown on plenty of occasions that he will score from the spot, should he be given the opportunity. He's scored five in his last three games and will no doubt be hungry to add to that tally.
One other stand-out threat, and certainly one to watch, is the man of the moment, on and off the pitch, Marcus Rashford. The England international is always a challenging opponent for any Premier League defence with his pace and skill, and with his eight goals already this season is in great form from out wide.
Last time this sides faced off was in July in a 2-2 draw as a last gasp strike from Micahel Obafemi saved the Saints from defeat following goals from Marcus Rashford, Anthony Martial and Stuart Armstrong - who opened the scoring in the twelve-minute.
The return fixture at St.Mary's also finished in a draw during the last campaign but on that occasion 1-1 with goals from Daniel James and Jannik Vestergaard. Although Southampton were down to ten men after Kevin Danso was dismissed in the 73rd minute.
Where to watch
The match will kick off at 14:00 on Sunday afternoon and will be broadcast live on Sky Sports Main Event and Sky Sports Premier League in the UK and Ireland. As always you can catch all the build-up, live coverage and reaction here on VAVEL.