United took the lead through Jadon Sancho’s opening goal at Old Trafford but, for the third straight game, were caught as Che Adams earned the Saints a deserved run to back up their midweek victory at Tottenham.
Ralf Rangnick recalled Cristiano Ronaldo to the starting line-up in the only change from the side that started the midweek draw against Burnley, while Southampton, unsurprisingly, remained with the same XI that beat Spurs .
Ronaldo nearly opened the scoring when played by Sancho and rounded the keeper, only to see his effort cleared down the line by Romain Perraud, while Adams slipped at the crucial moment to give the other a decent chance end.
Eventually it was Sancho who broke the deadlock as he came home from close range at the end of a superb counter-attack, Bruno Fernandes freeing Marcus Rashford to lay on a plate for his England team-mate.
Paul Pogba had the ball in the net in first-half stoppage time but the effort was rightly ruled out for offside against Ronaldo in the build-up and after the restart Adams timed his race to overtake David de Gea and away. Publish.
Fraser Forster was called on to deny Harry Maguire, Ronaldo and Diogo Dalot as United searched for an answer, while Stuart Armstrong wasted two good openings as Saints continued to threaten a shaky United backline.
Anthony Elanga and Jesse Lingard were sent on as United’s desperation grew, but Forster was Southampton’s hero, denying Harry Maguire a brilliant save in stoppage time.