The hosts took a first-half lead when Robin van Persie followed up to score after Wayne Rooney's effort had been blocked by goalkeeper Artur Boruc.
United hit the crossbar twice, through a Rooney shot and a van Persie header.
But their failure to kill the game off proved costly when Southampton grabbed a last-minute leveller, Dejan Lovren bundling in James Ward-Prowse's corner.
That result sees United fully 8 points behind leaders Arsenal who thrashed Norwich at the Emirates and Chelsea did likewise to Cardiff City. With Manchester City due to play West Ham saturday evening and Spurs at Aston Villa on Sunday the weekend could get worse yet for Reds fans.
United play Stoke City next saturday and a win to settle United nerves looks a must. What should be a run of the mill fixture will take on much bigger significance. Especially as it sees the return of United favourite Mark Hughes.