Left-back Gael Clichy is almost certainly out after suffering an ankle injury in the 5-0 win over Aston Villa on Saturday.
Midfielder James Milner (hamstring) could return but Jack Rodwell (hamstring) is unlikely to feature despite returning to training and right-back Micah Richards (knee) and centre-back Kolo Toure (ineligible) are out.
Real Madrid coach Jose Mourinho has selected a squad of 20 players for the game, which will see Cristiano Ronaldo return to Manchester for the first time since leaving United in 2009.
Karim Benzema should start up front after impressing against Athletic Bilbao at the weekend, with Gonzalo Higuain unavailable due to a hamstring injury.
Marcelo is sidelined with a broken foot, so Fabio Coentrao is in at left-back and Michael Essien, who is on loan from Chelsea, has not travelled after missing the win over Bilbao.