The Spain international, who has scored nine goals in the Premier League this season, is replaced in the starting lineup by Didier Drogba.
United boss Louis van Gaal has also made two alterations to his side, with Chris Smalling replacing the injured Phil Jones, while Marouane Fellaini is rewarded with a starting spot following his goalscoring exploits off the bench against West Bromwich Albion last time out.
Man United: De Gea, Rafael, Smalling, Rojo, Shaw, Blind, Fellaini, Mata, Januzaj, Di Maria, Van Persie
Subs: Lindegaard, Blackett, Fletcher, Carrick, Herrera, A.Pereira, Wilson
Chelsea: Courtois, Ivanovic, Cahill, Terry, Felipe Luis, Fabregas, Matic, Willian, Oscar, Hazard, Drogba
Subs: Cech, Zouma, Ake, Mikel, Baker, Salah, Schurrle
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