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 champions now without a win in four league games.
United have slipped to ninth in the table as a result – 13 points behind leaders 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 look to extend their outstanding record against Villa.
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"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 have lost just once to Villa in 33 matches – that defeat coming in December 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 have history on their 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 lie 11th in the table, just three points behind their opponents, but have been poor in front of their home fans this season.
They have won just seven points at Villa Park – only Sunderland have earned fewer at home in the Premier League – and scored just six goals at the venue in seven matches.
Despite having just 23 per cent possession at Southampton last week, they produced a great 3-2 win – a result that extended their 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.