Red Devils boss Jose Mourinho had hinted he would leave De Gea out as he looks to give Sergio Romero more game time ahead of the Europa League final.
Mourinho has also stated he will likely hand third-choice goalkeeper Joel Pereira a debut before the end of the season, and the Portuguese has been named on the bench at St. Mary's.
Such a move will only fuel speculation De Gea has played his final match for the Old Trafford outfit as reports linking him with a move to Real Madrid intensify.
United make four changes in total from their defeat to Tottenham last time out, with Henrikh Mkhitaryan, Marouane Fellaini and Matteo Darmian returning to the starting XI.
Axel Tuanzebe retains his place after impressing at White Hart Lane while Paul Pogba is missing from the squad altogether as he attends the funeral of his father.
Southampton, meanwhile, welcome back Manolo Gabbiadini after the striker was among a host of players rested for Saturday's win over Middlesbrough.
Southampton: Forster; Cedric, Yoshida, Stephens, Targett; Davis, Romeu, Ward-Prowse; Tadić, Redmond, Gabbiadini.
Manchester United: Romero; Jones, Bailly, Smalling; Darmian, Tuanzebe, Fellaini, Mata; Mkhitaryan, Rooney, Martial.