A Robin van Persie's brace either side of a Graziano Pellè goal, handed Southampton a third straight defeat and a second consecutive home loss.
Ronald Koeman named a strong side, minus the likes of Morgan Schneiderlin, Jack Cork, and Toby Alderweireld, who were all injured. Maya Yoshida and Sadio Mané was inserted into the line up, while young midfielder Jake Hesketh was given a place in the subs bench for the first time this season.
The match though started in the worst possible way when skipper José Fonte's poor back pass in the 12th minute was gobbled up by van Persie, who went on to slot the ball between Fraser Forster's legs.
But The Saints responded positively, Long put a header over the bar prior to the goal, while Pellè also had two chances to level the score. He headed wide from Steven Davis' corner, while moments later, a through ball from Duśan Tadić allowed the Italian a chance which he couldn't convert.
But Pellè eventually come good with a goal in the 31st minute. Davis drove forward and found Long, whose cross was then helped on by Tadić which allowed Pellè to smash it from close range.
United, despite their current run of form, doesn't look to be full of confidence, and they were handed a blow when Chris Smalling had to come off due to injury inside the first 20 minutes. Which was then followed by Paddy McNair coming off in the 38th minute.
Both sides had a chance each but neither Long or van Persie can capitalize. The latter struck a shot against the side netting, while the former skewed his shot over the bar.
Southampton begins the second half strongly, within the first 15 minutes, The Saints had two chances through Long and Pellè. But the Irishman's header was denied by David de Gea, while Pellè's shot, after he combined with Tadić, was high over the bar.
Southampton then was made to pay for their wastefulness in the 71st minute. The old adage of making a substitution while defending a set-piece seemed to be proven when Jake Hesketh came on to replace Tadić, with United going on to score less than a minute later.
Wayne Rooney's free kick found van Persie, who lingered at the far post, the Dutchman then put the ball away past Forster's legs once again to restore United's lead.
The last 20 minutes or so saw Southampton desperately looking for an equalizer, but to no avail. Nathaniel Clyne had two efforts which earned his side a corner late on, while another was just wide from outside the box.
Pellè could've had a second, but the striker's low shot across the goal was denied by De Gea once again, as United held on for all three points.
This result saw Southampton fall out of the top four, as they dropped to fifth place with 26 points. Up next is a trip to Turf Moor against Premier League's new boys, Burnley, on Saturday.