The midfielder will return to the starting 11 for the first time since United's victory over Sheffield United in the FA Cup on January 9, 2016 as they look to reach the fifth round of this year's competition.
Since his last start for United he was hit by injury trouble which truncated his 2015-16, and on his return from international duty at Euro 2016 was told by United boss Jose Mourinho that he was not needed by the club. However, he has since worked his way back into consideration after impressing the Portuguese with his professionalism.
Schweinsteiger featured in United's wins over West Ham and Reading in the EFL Cup and FA Cup respectively earlier this season, while Mourinho has suggested he is ready to recall the 32-year-old to the club's Europa League squad.
The German's selection is one of nine changes for the home side, with Luke Shaw and Anthony Martial among those back in the first XI after high-profile recent exclusions.
Wigan boss Warren Joyce names an unchanged side as he returns to Old Trafford for the first time since ending his eight-year association with United in the autumn.
Man Utd: Romero; Fosu-Mensah, Smalling, Rojo, Shaw, Fellaini, Schweinsteiger, Mkhitaryan, Mata, Martial, Rooney (c). Subs: J. Pereira, Blind, Tuanzebe, Herrera, Young, Ibrahimovic, Rashford.
Wigan: Haugaard, Buxton, Perkins, Power, Morsy, Grigg, Connolly, Macdonald, Jacobs, Warnock (c), Burn. Subs: Jaaskelainen, James, Kellett, Tunnicliffe, Morgan, Wildschut, Browne.