The Brazilian makes his fourth start of the Premier League campaign this season, while Robin van Persie also returns to Sir Alex Ferguson's side
Sir Alex Ferguson has made four changes following United's 4-1 victory over Fulham in the FA Cup fourth round on Saturday. Javier Hernandez misses out in attack as Robin van Persie is brought back in. Danny Welbeck is preferred to Nani.
Shinji Kagawa takes the place of Ryan Giggs in midfield, while in defence, Nemanja Vidic comes in at centre-back as Rafael drops to the bench.
Southampton boss Mauricio Pochettino has made two changes following his side's 0-0 draw with Everton on January 21.
Daniel Fox is preferred to Luke Shaw at left-back, while Jay Rodriguez moves into the team at the expense of Guly Do Prado.
Manchester United: De Gea, Jones, Smalling, Vidic (c), Evra, Carrick, Anderson, Kagawa, Rooney, Welbeck, Van Persie
Subs: Lindegaard, Rafael, Ferdinand, Valencia, Nani, Cleverley, Buttner
Southampton: Boruc, Clyne, Yoshida, Hooiveld, Fox, Puncheon, Cork, Schneiderlin, Ramírez, Lambert (c), Rodriguez
Subs: K. Davis, S. Davis, Lee, Lallana, Richardson, Shaw, Chaplow.