The Dutchman is sidelined for a month with a thigh injury as the Premier League champions look to avoid three straight domestic defeats when they travel to Villa Park on Sunday.
Successive home defeats against Everton and Newcastle United have ramped up the pressure on manager David Moyes, with last season's Premier League champion now without a win in four league games.
United has slipped to ninth in the table as a result – 13 points behind leader Arsenal – and will be without a host of key players for their road trip.
Robin van Persie (thigh) will miss the next month, Michael Carrick (Achilles) is still absent after surgery and fitness doubts over Marouane Fellaini (back), Chris Smalling (hamstring), Nemanja Vidic and Patrice Evra, who both have knocks, persist.
Moyes, who saw his side beat Shakhtar Donetsk 1-0 in the Champions League on Tuesday, feels he has the squad depth to cover their absence, though, as United looks to extend its outstanding record against Villa.
"I am sure we have plenty of players who can cover it (the injuries) and we don't miss them too much," Moyes said. "We want to play well. We've not done as well in the league as we should have. We want to put it right."
Since October 1999, United has lost just once to Villa in 33 matches – that defeat coming in Dec. 2009 when Gabril Agbonlahor's header gave Villa a 1-0 win at Old Trafford.
With 11 wins and six draws from their last 17 visits to Villa Park, United has history on its side.
The match will be the 500th club appearance of Wayne Rooney's career and he is currently on 149 Premier League goals for Manchester United.
Without last season's top scorer Van Persie, who scored a hat trick against Villa when the two sides met at Old Trafford in April, Rooney will be asked to lead the line up front and is in good form domestically, scoring three in as many matches.
Villa lies 11th in the table, just three points behind its opponent, but has been poor in front of iys home fans this season.
It has won just seven points at Villa Park – only Sunderland has earned fewer at home in the Premier League – and scored just six goals at the venue in seven matches.
Despite having just 23 percent possession at Southampton last week, it produced a great 3-2 win – a result that extended its unbeaten run to five.
But a 2-0 defeat at Fulham brought Villa back down to earth and they will be without midfield star Fabian Delph for this match due to suspension.
Ron Vlaar (calf) is set to miss out, while Libor Kozak (ankle) and Antonio Luna (groin) remain doubtful.
Joe Bennett (back), Charles N'Zogbia (calf) and Jores Okore (knee) remain on Villa's injury list.