Harry Maguire and Luke Shaw are major doubts for the Red Devils after they were both forced off in the 1-0 loss to Aston Villa on Saturday with respective calf and muscle injuries, with the latter potentially set for a lengthy spell on the sidelines.
Victor Lindelof is likely to come in for Maguire, though former Villarreal centre-back Eric Bailly will also be in contention, while Alex Telles is set to replace Shaw at left-back. Summer signing Raphael Varane will be the only defender who keeps his place from last weekend.
In midfield, Scott McTominay and Fred could retain their partnership, though Nemanja Matic and Donny Van de Beek – who both featured against Young Boys – will be hoping they can force their way into the first XI.
Mason Greenwood, Bruno Fernandes and Paul Pogba are expected to start again in advanced midfield roles, which will likely see Jadon Sancho, Jesse Lingard and Anthony Martial begin on the bench once again.
Cristiano Ronaldo will break Iker Casillas' record for the most Champions League appearances in the competition's history if he features on Wednesday, setting a new record of 178 games. The Portuguese legend has never scored against Villareal in four previous matches against them in Europe's elite club competition.
Manchester United possible starting lineup: De Gea; Dalot, Lindelof, Varane, Telles; McTominay, Fred; Greenwood, Fernandes, Pogba; Ronaldo