The Frenchman ensured parity at the break by cancelling out Graziano Pelle's opener, before capitalising on a Maya Yoshida error early in the second half to put the visitors 2-1 ahead.
Juan Mata then finished a 45-pass move to put United in a commanding position, with Pelle adding a second for the hosts to ensure a nervy finish, but the Red Devils held on.
We've already had one managerial feud this weekend. How about another? Yep, Ronald Koeman and Louis van Gaal lock horns and renew hostilities when Southampton host Manchester United at St Mary's. Granted, it may seem softer than Niall Horan throwing a slipper at Ronan Keating, but actually, this one has a bit of history. Is it as spicy and vitriolic as Arsene Wenger and Jose Mourinho's tiff? Perhaps not, but it certainly stretches back just as far. Let's have a quick look at the decline in the relationship of the once-good friends before team news.
So, it's 2004. Both men are reunited at Ajax, with Koeman previously being assistant to Van Gaal at Barcelona. This time, Koeman is the head coach and Van Gaal is technical director. Legend has it - actually, the Southampton manager confirmed all of this - that the now-Red Devils coach was interfering with team affairs, regularly attending training sessions and applauding the players which he liked. From there, their relationship has been colder than a walk beyond the wall.
Van Gaal was later rather dismissive of his compatriot, referring to him as "that boy" in his autobiography. He also stated that Koeman was not his first choice to succeed him at AZ Alkmaar in 2009. As we know, both landed in English football last summer but, despite pre and post-match handshakes, there was no traditional glass of wine afterwards. Koeman says that Van Gaal snubbed him in both meetings last term - both managers secured one win apiece.
Frosty, eh? Anywho, let's leave them to it and focus on the players now. Speaking of which, shall we have a quick check on the team news? Why not. First, though, have a look at what the boys down at Sports Mole HQ have had to say on this one and we'll meet again in a few minutes.
We'll start with the Saints.Graziano Pelle, who scored in Southampton's 2-1 defeat here last term, spearheads the attack. Maya Yoshida replaces Cedric Soares at right-back, while Steven Davis makes way for Oriol Romeu, who sits in a midfield two with Slick Victor Wanyama. Might not be his nickname. Also, Sadio, the Radio, Mane comes back into the fold. Again, may not be his real nickname. He replaces Jay Rodriguez and he'll be keen to show United what they could have had in the summer.
And United? Well, Wayne Rooney returns after missing the last two games through injury. This is his first outing since breaking England's all-time goalscoring record. There's also a spot up front for Anthony Martial after his debut goal last week. Further back, Memphis Depay starts on the left, with Juan Mata on the left. Michael Carrick and ex-Saint Morgan Schneiderlin sit in the middle of the park. Daley Blind moves over to left-back to cover Luke Shaw, who could be out until May, while Marcos Rojo joins Chris Smalling at centre-half. David de Gea between the sticks once more.
Let's look at the head-to-head stats, shall we? Southampton beat the Red Devils at Old Trafford in January for their first away win at United since, hmm, 1988! That was the year I was born incidentally. However, United won the reverse fixture 2-1 here at St Mary's, with Jose Fonte hardly covering himself in glory that day if memory serves.
Ominously, the Saints have lost more times against Manchester United than any other Premier League side. They've only lost 22 times! Quite famously, they did win 6-3 at The Dell back in the 1996-97 season in a game that saw the visitors change shirts at half time. Almost 20 years ago this. Time flies when you're winning titles.
Dusan Tadic struck the winner at Old Trafford earlier this year and pulled out what is now known as the Mario Balotelli. Then he started playing like him sadly.
PREDICTION! Right, we're just, hmm, 20 minutes from kickoff! Time to get a prediction wrong and we fancy a 2-1 United win, just like last season. Scorers? Hmm, let's go for Memphis and Rooney, both of whom are certainly due a Premier League goal. Pelle to score for the hosts.
Here's a bold one. Not content with just predicting the scoreline, or indeed the goalscorer, this fellow has only predicted the minutes in which both goalscorers will score.
Not sure if I've tweeted my prediction yet but
Southampton 2-0 United
Pelle 18'
Rodriguez 71'
Right, kickoff is in just seven minutes time. Join us then for what will hopefully be a cracker. It's been a controversial weekend for the Premier League, what with nine-man Arsenal losing at Chelsea, West Ham winning at Man City etc, so hopefully this one makes headlines for the right reasons.
Eek. That was a bit awkward between Van Gaal and Koeman. They shake hands, and they're right beside each other, but Koeman is just ignoring him and talking to someone on Van Gaal's staff while the latter stood around like a spare you know that. Anywho, lets go.
We said it was Blind at left back but it's actually Rojo. Blind is beside Smalling at centre-back. Koeman says that he would exploit the Dutchman's defensive frailties so let's see if that materialises. United with all the possession so far.
The brightest moment of this first nine minutes has been Rojo's pink boots. Other than that, it's been a little dull if we're being truthful. It's a chess match.
SHOT! It's excellent work from Pelle down the right-hand side. The Italian crosses for Mane, whose headed knock-down finds Tadic and the Serbian, who scored the winner in January, volleys wide of De Gea's goal. The game needed a moment like that.
What a start by the Saints. James Ward-Prowse whips an excellent ball into the six-yard box as Mane, who squeezed between Smalling and Blind, looked certain to score but De Gea pulls off a fantastic instinctive save. However, the rebound falls to Pelle, who taps home from close range to open the scoring. Game on!
OFF THE POST! Oh my word United just haven't started and De Gea is furious. Smalling's dodgy ball out from the back is pounced on by Romeu, who plays in Pelle. He does excellently to create the pace for a shot and a second goal looks certain, but he passes against the outside of the post.
SHOT! Here's United's first shot, and it's man of the moment Martial, who turns and shoots over the bar from the outside of the box. Southampton fans loved that.
SHOT! Southampton have been excellent in this first 20 minutes and Ward-Prowse, arguably the best player on the pitch, tries to beat De Gea with the outside of his boot but De Gea does well to stop it.
CHANCE! Wow this is a chance for United, as Mata finds the run of Memphis, who ran beyond Yoshida, but his header is well over. Should've tested Stelekenburg at least.
Pelle is absolutely bullying Daley Blind, as Koeman said he would in his pre-match spiel. The Italian knocks it around his Dutch counterpart before playing in Mane, whose pull back for Ward-Prowse is decent but Rojo brings him down. Clattenburg waves away.
He's done it again! Eight days after exploding on to the scene in the 3-1 win over Liverpool, the Frenchman, 19, does it again. Rooney plays in Mata despite a suspicion of offside, with the Spaniard then squaring to Martial. He feigns to shoot on his left before turning brilliantly and poking him with his right. Superb composure.
Southampton will feel unlucky; not only because it was offside, but because they looked in complete control. They'll need to go again. A goal wasn't exactly coming for United, but it was looking more likely because Southampton had stopped playing a little.
Five minutes until the break and Southampton looking ever so shaky in the dying minutes of this half. Van Dijk pokes the ball away from Mata at the vital moment. Good defending, but Fonte is having a shocker.
Well, that's all she wrote in that half. Superb bit of composure from Martial put United back on level terms following a poor start, in which Pelle tapped them ahead. Southampton were much better for large spells but United, to their credit, came back well.
KICKOFF: And we're back underway. Two subs to tell you about - Cuco Martina replaces left-back Matt Targett, while Antonio Valencia replaces United right-back Darmian.
The Targett change was forced for Southampton, with the left-back struggling before the break, but the United change was tactical I'm hearing. I have spies on the United bench.
What a mare by Yoshida! His back pass is severely underhit and Martial takes full advantage, slotting past Stekelenburg. Fine finish but Yoshida will hang his head.
CLOSE! United look in the mood now and Memphis, from about 30 yards, drills just wide of the Southampton goal. The hosts look very, very out of sorts now.
Southampton just coming into it a little bit more now in recent minutes, but they're nowhere near as dangerous as they once looked sadly. Dare I suggest that United are comfortable.
WHAT A SAVE! We said United were comfortable but Southampton would have made me eat my words if not for De Gea, who pulls off a brilliant finger-tip save to keep out Fonte's header. Wow.
This is worrying from a Southampton perspective but, despite nearly scoring, they're not building on it. It's all United once again. There's certainly more goals in this - but I'm not sure if Southampton can score. Even when they do get through United's defence, they've got De Gea to beat!
United are just passing Southampton to death here. They're chasing shadows. If they score from this move I guarantee it'll be at least 60 passes. The hosts can't get it back.
Oh my word this is a ridiculous amount of passes. We must be talking at least 40. The ball comes to Depay, who does well to trick Fonte before firing against the post, but the ball comes out for Mata and he casually slots into an empty net.
PENALTY APPEAL! Mane goes down inside the area under a challenge from Smalling, but nothing doing. Clattenburg waves away. This isn't looking great for Southampton.
We're into the final 12 minutes and Southampton don't look at it any more. Still, all they need is one an that would make it a very, very nervous last quarter for the visitors. Problem is they can't get the ball.
We said Southampton only needed one to make it a nervy finale and it looks like we're in for just that. Blind isn't tight enough to Mane, who stands up a wonderful cross for Pelle to plant past De Gea. Game on.