United manager Louis van Gaal bemoaned his side's injury problems after Ashley Young became the latest member of his squad to face a lengthy spell on the sidelines.
The winger turned full-back left the field with a groin injury shortly before the break at Anfield with a groin problem which has proved to be much worse than first thought.
Young joins Marcos Rojo, Michael Carrick, Bastian Schweinsteiger, Luke Shaw, Phil Jones and Antonio Valencia on the treatment table ahead of the visit of Ronald Koeman's Southampton side.
Adnan Januzaj is available and looks set to at least be on the bench following a brace for Warren Joyce's Under 21 side.
Speaking on Friday, Van Gaal praised captain Wayne Rooney and also admitted that the injuries may force his hand in this month's transfer market.
The Dutchman said:
"I am very happy with Wayne because it is a fact that since he is scoring we have won our games, with one draw at Newcastle, so the responsibility for the result and commitment for the result is very important and all the players are showing that, not just Wayne.
"I think the pressure is gone a little bit but it we would return if we do not beat Southampton so it is always the same pressure for Manchester United- we have to win.
"Our fans are always expecting us to win especially when we are at home against a team that is not a competitor.
"The level of Manchester United is high, and to play at level every week is difficult for young players which is why we have to look always in this transfer period for replacements.
"It shall not be easy because the clubs do not want to sell at this moment and that is our problem but we are looking and you have to wait and see."
Southampton picked up their first Old Trafford win in 27 years in last season's corresponding fixture on their way to a highest ever Premier League finish of seventh and arrive for this term's tussle in a comfortable mid-table position of tenth.
Inconsistent form has been the south coast's side main problem this season, with wins over Arsenal and Chelsea offset by a disappointing defeat at Norwich, a home draw with basement boys Villa and an FA Cup third round exit to Alan Pardew's Palace.
Despite their indifferent form, the Saints certainly have the capability to test the Reds at Old Trafford, having taken four points from their previous two visits to our place.
Charlie Austin could make his debut for the Saints at Old Trafford after his £4m move from QPR, where he scored 18 top flight goals last season.
Form guide: United L D W W D W Southampton W L L L W W
Match odds: United 10/11 Draw 11/5 Southampton 7/2
Referee: Mike Jones