Southampton were defeated as they took to the road for the first time this season.
Claude Puel's men travelled to Old Trafford to take on Manchester United as JosÚ Mourinho took charge of a Manchester United side which had Eric Bailly, Paul Pogba and Zlatan Ibrahimovic making their competitive home bows.
There were just two changes to the Saints side which drew 1-1 at home to Watford last weekend, with JosÚ Fonte stepping in to replace Maya Yoshida and Pierre-Emile H°jbjerg selected ahead of James Ward-Prowse.
Oriol Romeu was an unfortunate early casualty, exiting after just nine minutes to be replaced by Jordy Clasie after pulling up with an injury.
Pogba yielded the first chance of the game when he whipped an effort towards Fraser Forster's near post, but the England stopper was equal to the midfielder's effort.
Nathan Redmond almost found DuÜan Tadić with an inviting cross on the break, before Shane Long sent an effort into the side-netting after turning away from his marker.
Saints were almost immediately punished, with Zlatan Ibrahimovic rising highest to send a thumping header past Forster after Wayne Rooney was allowed too much time to provide the cross.
Long almost turned home a Matt Targett cross as Puel's side went in search of an equaliser, with Tadić seeing a goal ruled out soon after.
Saints were stung again just seven minutes into the second half, with Clasie adjudged to have fouled Luke Shaw, enabling Ibrahimovic to tuck away the resulting penalty.
Ultimately the penalty seemed to kill the contest, with Mourinho's side content to keep bodies behind the ball and frustrate Southampton, while looking to find a third goal on the counter.
Virgil van Dijk twice provided timely blocks to deny Anthony Martial and Shaw, but Saints were unable to haul themselves back into the tie and left Old Trafford with nothing to show for their performance.
SAINTS: Forster; CÚdric, Fonte, Van Dijk, Targett; Romeu (Clasie - 9'); H°jbjerg, Davis (Austin - 67'); Tadić; Long (Rodriguez - 84'), Redmond.
Unused Subs: McCarthy, Pied, Yoshida, Ward-Prowse.