Erik ten Hag's men thumped Real Betis 4-1 in the first leg of their Europa League last-16 tie on Thursday, while the Saints most recently edged Leicester City 1-0 to move off the foot of the table.
Match preview
Seemingly trying to prove a point by putting out the same 11 players who capitulated in their 7-0 defeat to Liverpool at Anfield, Ten Hag got exactly the reaction that he wanted against Betis, who felt the full force of the Red Devils' affinity for goalscoring at the Theatre of Dreams.
Marcus Rashford's 25th goal of the season preceded a well-taken Ayoze Perez equaliser before the break, but Man United came out for the second half a different beast, as Antony, Bruno Fernandes and Wout Weghorst gave the Red Devils a three-goal cushion to take into next weekend's second leg.
While Ten Hag's crop have one foot firmly in the quarter-finals of Europe's secondary competition, the EFL Cup champions can surely consign any faint hopes of a Premier League title charge to history, as last weekend's humiliating Merseyside mauling left them 14 points adrift of leaders Arsenal in third place, albeit with a game in hand.
Nevertheless, with crisis club Tottenham Hotspur still four points behind having also played a game more, Man United's podium spot is in no real danger for the time being, and few foes have come away from Old Trafford with anything other than their tails tucked between their legs.
Indeed, victory over Betis stretched Man United's unbeaten run at the Theatre of Dreams to a staggering 20 games, and they have scored at least two goals in each of their last 15 home matches, but visiting managerial novice Ruben Selles has previous when it comes to defeating Big Six sides on their own territory.
From the highs of sinking Chelsea to the lows of losing to Leeds United and Grimsby Town, Selles has already gone through all the emotions that come with managing Southampton, but there was a buoyant vibe at St Mary's when Leicester came to town last weekend.
Taking full advantage of the Foxes' inability to register a single shot on target, Southampton struck in the 35th minute through January signing Carlos Alcaraz before the Argentine came off injured, demoting South-coast rivals Bournemouth down to 20th place in the process.
The 19th-placed Saints are only clear of the Cherries on goal difference, but just one point separates them from Leeds in the safety of 17th spot, while West Ham United and Leicester are also within touching distance and could be usurped by their fellow basement battlers in the not-so-distant future.
The St Mary's crowd does not always act as a stimulus for Southampton, though, as 12 of their 21 points in the 2022-23 Premier League season have actually come on the road - no other team in the division has won more than half of their points on rival territory this season.
However, a second-half Fernandes effort was all that it took for Man United to prevail 1-0 at St Mary's back in August, extending the Red Devils' unbeaten run over Southampton to 14 matches since Charlie Austin silenced the Old Trafford crowd in January 2016.
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Southampton Premier League form:
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Team News
Man United midfield duo Donny van de Beek and Christian Eriksen are continuing their lengthy recoveries from knee and ankle issues respectively, while Anthony Martial is back in full training from a hip problem but is unlikely to be considered for selection from the first whistle.
Ten Hag must also assess the fitness of Marcel Sabitzer, who was unavailable against Betis due to a knock, and it would not be a shock to see the hosting manager consider a couple of alterations given that his side have fewer than 72 hours to recuperate.
Aaron Wan-Bissaka and Tyrell Malacia could both threaten to disrupt the harmony in the full-back areas, and unless Harry Maguire comes in for a rare start, Fernandes will continue to don the captain's armband after redeeming himself on Thursday night.
Meanwhile, Southampton boss Selles quickly downplayed the severity of Alcaraz's knee sprain following his 50th-minute withdrawal against Leicester, and the 20-year-old should be fit enough to take his rightful place in the first XI here.
Alcaraz'z swift return would leave Valentino Livramento and Juan Larios as the visitors' only two injury absentees, and Selles should see no reason to deviate from the XI that got the job done against a shot-shy Leicester.
However, a squandered spot kick from dead-ball specialist James Ward-Prowse last weekend saw the Saints captain make it two missed penalties from two attempts in the top-flight this term, and the midfielder could now - somewhat surprisingly - become the first Southampton player to miss three in a Premier League campaign.
Manchester United possible starting lineup:
De Gea; Wan-Bissaka, Varane, Martinez, Malacia; Casemiro, Fred; Antony, Fernandes, Rashford; Weghorst
Southampton possible starting lineup:
Bazunu; Maitland-Niles, Bella-Kotchap, Bednarek, Walker-Peters; Ward-Prowse, Lavia; Walcott, Alcaraz, Sulemana; Adams
We say: Manchester United 3-0 Southampton
Despite experiencing their fair share of miserable away-day fortunes in recent memory, Man United need no second invitation to turn up the heat at Old Trafford, where Southampton should become the latest victims of Ten Hag's cunning attackers.
An affinity for performances on the road may offer the Saints a small glimmer of hope, but we do not expect any surprises to be sprung at the Theatre of Dreams as Man United refuse to give up on their own title dream.