Robin van Persie netted a hat-trick to take his Premier League tally to 100 goals as the Red Devils twice fell behind before scoring two goals in five minutes to produce a massive victory over an unlucky Saints outfit.
Against the script, Southampton took the lead in the 16th minute when main man Rickie Lambert got on the end of Jason Puncehon's left-footed cross from the right to powerfully head home past Anders Lindegaard, who was preferred to David de Gea, at the back post.
But soon enough parity was restored as United's newest ace van Persie superbly controlled Antonio Valencia's rightwing cross from the right to then place his left-footed effort across Kelvin Davis, who got a glancing leg to the ball, and in for his second goal in his second start for the club.
Nigel Adkins' Saints side were working tirelessly throughout and got another reward when Lambert received the ball from Puncheon before sitting it up for an advancing Morgan Schneiderlin to make the most of Patrice Evra's slip and head home for a second for the home team.
But just as the Saints thought they had come away with a rare win over United, van Persie bobbed up to score an equaliser with a few minutes left when Rio Ferdinand's header hit the upright to see the former Arsenal star fire home from close range from the deflection off the woodwork.
In injury-time, van Persie gave United maximum points when he got free at the edge of the six-yard box to glance home a header from Nani's corner to send last season's runners-up to fifth position on the table.
With just over 20 minutes remaining, Southampton gave away a penalty when Jos Hooiveld slid in behind on van Persie with referee Mike Dean having no hesitation in making the decision, however, Davis was able to keep out the Dutchman's chipped attempt from the spot.
In the end, however, van Persie saved the day for United to endear himself to his new fans as the Saints remained at the foot of the top flight table.
St Mary's Stadium, Southampton - 31,609
Yellow cards:SOU - Jos Hooiveld 68' MU - nil