A goal in each half from Robin van Persie inflicted a second home defeat of the season on Saints, who were unfortunate to lose a game they had the better of.
Van Persie, who masterminded United’s 3-2 victory at St Mary’s two seasons’ ago, was the thorn in Southampton’s side once again, with his clinical finishing from close range making the difference in this encounter.
It was a harsh result on Ronald Koeman’s men, with Saints having enjoyed most of the possession and creating the better chances. They gifted United a twelfth minute lead though, when Fonte’s weak pass was pounced upon by Van Persie, who calmly slotted the ball into the net against the run of play.
Saints levelled up through Graziano Pellè’s first goal in six games, moving him up to ten strikes in all competitions to make it 1-1 at half-time.
Van Persie restored United’s lead on 71 minutes with a prod home at the far post from Wayne Rooney’s searching free-kick, which gave the visitors their fifth straight win in the Barclays Premier League.
Toby Alderweireld joined Jack Cork and Morgan Schneiderlin as injury victims for the night, with Maya Yoshida and Sadio Mané each coming into the side.
Saints also named young Academy midfielder Jake Hesketh in the matchday 18 for the first time.
Rooney and Van Persie got the match under way, with Saints attacking the Northam stand on a cool and clear evening inside St Mary’s.
The hosts began brightly too, with Ryan Bertrand delivering a cross from the left which Shane Long headed over the top from the right side of the area.
For all their endeavour and high spirit, Saints suffered a blow on 12 minutes, which to make matters worse, was self-inflicted. José Fonte’s under-hit pass back to Fraser Forster was seized upon by Robin van Persie, who read the situation perfectly to slot the ball through the goalkeeper’s legs for a lead United gained through their first shot of the match.
Koeman’s men responded well though, with Pellè heading an effort wide at the near post from Steven Davis’s corner, with the Italian then going close to playing Dušan Tadić through on goal soon after, but the Serbian couldn’t make the most of the through-ball.
Saints continued to improve, with Tadić reverting to an assist for Pellè, with the striker’s low shot at the left post saved at the near post by David De Gea.
That proved as the warning sign to Saints’ deserved leveller on 31 when the same combination this time drew a goal. A move which owed much to the desire of Steven Davis, the midfielder’s drive to get forward found Shane Long, whose cross into the area was helped towards goal by Tadić, and smashed home by Pellè into the roof of the net for 1-1.
United slowed up and having already lost defender Chris Smalling to an early injury, they replaced Paddy McNair with Ander Herrera to try and bolster the support for their backline.
Saints went close to turning the game on its head in the 35th minute when Shane Long screwed a shot over the angle of the upright and the hosts ended the half firmly in the ascendancy, though United had the last say of the 45 with a rising strike from Van Persie who crashed a rising shot into the side netting.
The hosts maintained their superiority into the new half. Yoshida advanced into the area before losing out inside the six yard box to a last ditch challenge from Jonny Evans.
Koeman’s team turned the screw when Davis drove forward once more and this time he found Tadić, whose cross was headed at goal by Long with De Gea making a solid save at his near post.
Saints went close again on 59 minutes when Pellè and Tadić made another short link up, with the former placing a shot over the bar from the edge of the area.
The contest had opened out even further with United’s tendency to try and catch Saints on the break, though Fonte and Yoshida stood up to the challenge of Rooney and Van Persie’s endeavour.
Tadić was replaced by senior debutant Jake Hesketh who came on for his professional debut, but less than a minute later, United incredibly retook the lead.
Van Persie celebrated his second strike of the game as he lingered at the far post to reach Rooney’s arching free-kick from the left flank, with the Dutch striker poking the ball through Forster’s legs for the second time in the match for 2-1.
Saints responded well again with Mané playing Pellè into the area on the left, with the striker seeing a low shot across goal impressively turned away by De Gea.
Emmanuel Mayuka was introduced for the final ten minutes or so to try and force another equaliser with United still not looking convincing value for their lead.
Nathaniel Clyne twice drove efforts towards goal, with the latter earning the hosts a corner late on, but that would be the closest the hosts came to testing De Gea, as United held on for the win.
Southampton team: Fraser Forster, Nathaniel Clyne, Maya Yoshida, Jose Fonte (c), Ryan Bertrand, Steven Davis, Victor Wanyama, Dušan Tadić (Jake Hesketh 70), Shane Long (Emmanuel Mayuka 79), Sadio Mané, Graziano Pellè
Unused substitutes: Kelvin Davis, Florin Gardos, Llloyd Isgrove, Harrison Reed, Matt Targett
Goal: Pellè (31)
Booked: Mané (89), Fonte (90)
Manchester United team: David De Gea, Marcos Rojo, Chris Smalling (Jonny Evans 18), Paddy McNair (Ander Herrera 39), Michael Carrick, Ashley Young, Marouane Fellaini, Antonio Valencia, Juan Mata (Darren Fletcher 88), Robin van Persie, Wayne Rooney (c)
Unused substitutes: Anders Lindegaard, Radamel Falcao, Adnan Januzaj, James Wilson
Goals: Van Persie (12) & (71)
Booked: Rooney (90)
Referee: Kevin Friend
Attendance: 31,420 (including 3,164 away)