Harry Maguire, Jesse Lingard, Anthony Martial and Luke Shaw all have issues ahead of the first-leg showdown at Old Trafford, and Reds boss Ole Gunnar Solskjaer looks set to leave it until the last moment before deciding on his starting eleven.
At this stage of the competition and with Solskjaer chasing a piece of silverware against their city rivals, the Norwegian is likely to field a strong side, but he could be restricted to a certain extent.
Maguire injured a foot in the weekend's goalless FA Cup draw at Wolves but managed to soldier on and play the full 90 minutes.
The decision to play on could backfire and it remains to be seen if he will start against City.
Lingard, Martial and Shaw all missed the match because of illness, while Tahith Chong appeared to pick up a knock at Wolves and is a doubt.
Paul Pogba's ankle problem has sidelined him for a month while fellow midfielder Scott McTominay (knee) is absent for longer while Eric Bailly, Axel Tuanzebe and Timothy Fosu-Mensah may not yet be ready to return.
City boss Pep Guardiola has close to a fully-fit squad to pick from with defender Nicolas Otamendi back in contention after recovering from a knock.
Centre-back Aymeric Laporte and winger Leroy Sane, who have both had long-term knee conditions, are the only major absentees but both are well on course to return.
A number of players were rested at the weekend as City beat Port Vale in the FA Cup, but could return against United.
They include star players such as Ederson, Kevin De Bruyne, Raheem Sterling, Gabriel Jesus, Kyle Walker, Rodri and Fernandinho.