The Ecuador international is replaced in the starting XI by Ryan Giggs, while Robin van Persie returns to the side after scoring from the bench against West Brom on Saturday
The Dutchman came on as a substitute against West Brom at the weekend, and sealed the tie with a late goal, but comes in for Danny Welbeck.
Sir Alex Ferguson makes two changes in defence with Rafael Da Silva and Jonny Evans coming in for Chris Smalling and Nemanja Vidic, who both drop to the bench, while Shinji Kagawa is among the replacements, with Chicharito taking his place in the team.
Wigan make just one alteration to the side that beat Aston Villa 3-0 at the weekend, as James McArthur comes in for David Jones in midfield.
Wigan: Al Habsi; Ramis, Caldwell, Figueroa; Boyce, McCarthy, McArthur, Beausejour; Di Santo, Kone, Maloney
Subs: Pollitt, Jones, Gomez, McManaman, Boselli, Stam, Golobart.
Manchester United: De Gea; Rafael, Ferdinand, Evans, Evra; Young, Carrick, Cleverley, Giggs; Van Persie, Chicharito.
Subs: Lindegaard, Valencia, Smalling, Vidic, Welbeck, Scholes, Kagawa.