United too kicked off their season with a loss, as they were beaten 1-0 by Everton in Liverpool.
Southampton are likely to be without Guilherme do Prado because of the midfielder's off-pitch indiscretions, while summer signings Maya Yoshida and Gaston Ramirez are unlikely to start.
United should deploy the same starting lineup as against Fulham last weekend. Defender Jonny Evans featured for the reserves in midweek but Ferguson is unlikely to start him at centre-back.
Striker Wayne Rooney is out for four weeks with a leg injury.
Southampton: Davis, Clyne, Hooiveld, Fonte, Fox, Davis, Schneiderlin, Lallana, Rodriguez, Lambert, Lee
Manchester United: De Gea, Rafael, Carrick, Vidic, Evra, Cleverley, Anderson, Valencia, Kagawa, Young, Van Persie
Sports Mole says: 1-3