The Spanish keeper is dropped after his error gifted Fulham a goal last week whilst the former England defender and Danny Welbeck return to the starting XI
The Spaniard was involved in a mix-up with captain Nemaja Vidic in United's 3-2 win over Fulham last time out and has seemingly paid the price for the error with Anders Lindegaard coming in to replace him.
Serbian defender Vidic keeps his place however, and will start alongside familar partner Rio Ferdinand who has recovered from injury to start at the heart of the Red Devils defence.
The other change sees striker Danny Welbeck come in to partner Robin Van Persie in attack.
For the home side, 17-year-old Daniel Ward-Prowse comes back into the side.
Southampton: K Davis, Clyne, Fox, Fonte, Hooiveld; Puncheon, S Davis, Lallana, Schneiderlin, Ward-Prowse; Lambert.
Subs: Gazzaniga, Rodriguez, Lee, Do Prado, Richardson, Mayuka, Seaborne.
Manchester United: Lindegaard; Rafael, Vidic, Ferdinand, Evra; Cleverley, Carrick, Kagawa; Valencia, Van Persie, Welbeck.
Subs: De Gea, Evans, Giggs, Hernandez, Nani, Scholes, Powell