With Matteo Darmian (chest), Ashley Young (groin), Marcos Rojo (shoulder), Antonio Valencia (foot) and Luke Shaw (leg) injured, United are short in numbers at the back so 22-year-old Varela looks set to keep his place in the team following his impressive performance in the 3-1 FA Cup win at Derby on Friday.
Cameron Borthwick-Jackson is expected to start on the other side of defence on his 19th birthday, but midfielder Bastian Schweinsteiger (knee) and defender Phil Jones (ankle) are unavailable.
Forwards Marko Arnautovic and Jonathan Walters will return to Stoke's squad for the trip to Old Trafford.
The pair, plus full-back Glen Johnson, all missed the weekend FA Cup defeat to Crystal Palace because of minor injuries but have recovered sufficiently to be included.
Defender Marc Wilson has been ruled out for 10-12 weeks after injuring a medial knee ligament at Selhurst Park.
Man United squad: De Gea, Romero, Varela, Borthwick-Jackson, Smalling, Blind, McNair, Schneiderlin, Herrera, Carrick, Fellaini, Depay, Lingard, Mata, Januzaj, Pereira, Martial, Rooney, Keane.
Stoke squad: Butland, Johnson, Wollscheid, Muniesa, Pieters, Whelan, Afellay, Shaqiri, Walters, Arnautovic, Bojan, Haugaard, Bardsley, Van Ginkel, Ireland, Joselu, Crouch, Biram Diouf
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