The Red Devils move seven points clear at the top of the Premier League while a first defeat in six games leaves the Saints only three points above the relegation zone
Jay Rodriguez capitalized on a mistake from Michael Carrick to give the Saints a shock early lead but a double from Wayne Rooney had the hosts in front by halftime.
The Saints improved in the second half with Rickie Lambert testing David De Gea on a couple of occasions but the league leaders were worth their win despite a nervy end.
Sir Alex Ferguson reinstated Robin van Persie back into his attacking looking starting line-up, with Danny Welbeck, Shinji Kagawa and Rooney supporting the Dutchman in attack, while Nemanja Vidic returned in defense.
Mauricio Pochettini made two changes from the draw against Everton, Danny Fox and Rodriguez replaced Luke Shaw and Guly do Prado.
The hosts got off to an awful start when Michael Carrick's backpass put David De Gea in all sorts of trouble, Rodriguez pounced on the United shot-stopper, taking a touch to beat him before passing it into an open net in the third minute.
The Saints' lead didn't last long, however, as Rooney fired United level five minutes later when he timed his run on to Kagawa's lobbed pass and stroked the ball easily past Artur Boruc.
The Japan international was involved again moments later, getting down the left flank and cutting inside before striking a shot on to the near post.
Southampton was pegged back in its own half from then on and could only hold off the Red Devils' attacking onslaught until the 27th minute.
Van Persie drifted a deep free kick towards Boruc's back post where Evra was on hand to head the ball back across the box for Rooney to turn into the net from a yard out.
The Saints started the second period brightly with Rickie Lambert making De Gea make is his first save with a tame volley.
Southampton continued to apply pressure on the hosts and could have gone ahead on the hour mark when Lambert hit the target with a fierce free kick. De Gea spilled the initial effort but managed to clear before Adam Lallana could pounce on the loose ball.
United weathered the Saints' storm and then created some chances of its own with Rooney and Kagawa combining to drive Sir Alex Ferguson's side forward.
Van Persie thought he had added his name to the scoresheet in the 75th minute when he headed past Boruc at the second time of asking but the Dutchman had his celebrations cut short by a harsh offside decision.
Lambert then came close to grabbing the equaliser with another free kick; the Saints' striker curled an effort perfectly over the wall only to see De Gea make an outstanding low save.
Rooney then wasted a chance to seal his hat-trick when he was slid through by Van Persie but the England forward took a bad touch allowing Boruc to smother.
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