Manchester United boss Erik ten Hag has made two changes from Thursday’s Europa League win over Real Betis.
Aaron Wan-Bissaka and Jadon Sancho come in for Diogo Dalot and Fred, who both drop to the bench.
It means Sancho makes a first Premier League start at Old Trafford since October.
Bruno Fernandes captains the side and he looks set to play a deeper midfield role alongside Casemiro.
Antony Martial, meanwhile, has not made the matchday squad despite resuming training with the main group after returning from injury.
Southampton team news – Alcaraz starts | Perraud in for Maitland-Niles
Team to play Man Utd: Bazunu; Walker-Peters, Bednarek, Bella-Kotchap, Perraud; Ward-Prowse, Lavia; Walcott, Alcaraz, Sulemana; Adams.
Subs: McCarthy, Caleta-Car, A Armstrong, Onuachu, S Armstrong, Mara, Salisu, Elyounoussi, Diallo.
Man Utd team news – Sancho and Wan-Bissaka start
Team to play Southampton: De Gea; Wan-Bissaka, Varane, Martinez, Shaw; Casemiro, Fernandes; Antony, Weghorst, Sancho; Rashford.
Subs: Heaton, Maguire, Malacia, Fred, Dalot, Pellistri, McTominay, Garnacho, Mainoo.