It’s actually the Saints who go into the game as the form team, having lost just once in all competitions since mid-December.
And Ralph Hasenhuttl’s side will be in a buoyant mood on the back of an exciting 3-2 win at Tottenham on Wednesday night.
It's actually Southampton who will go into the game with a higher morale having moved into the top half of the table in midweek.
Having gone a goal behind at the Tottenham Hotspur Stadium through Jan Bednarek’s own goal, Saints showed great character to fight back, and could have had more than Armando Broja’s strike to show for their efforts at half-time.
However, Spurs regained their lead after 70 minutes through Son Heung-Min, before the visitors stunned Antonio Conte’s side.
Mo Elyounoussi headed Saints level before Che Adams stooped to nod home James Ward-Prowse’s cross three minutes later to send the travelling support into ecstasy.
Frustrations continue to grow at Old Trafford, with the Red Devils missing the chance to move into the top four after being held to a 1-1 draw by Burnley in midweek.
Paul Pogba’s first half effort put United ahead at Turf Moor, but only for Jay Rodriguez’s effort minutes after the break to earn the relegation battlers a point.
But it was the manner of the draw which would have frustrated United supporters, with Rangnick’s men failing to produce a shot on target in the second half.
Ones to watch
Jadon Sancho's performances in recent weeks are beginning to show what a talent he is. After scoring a fine goal against Middlesbrough in the cup, the England winger was voted man of the match in the 1-1 draw with Burnley.
Although the conditions were far from perfect at Turf Moor, he still looked one of the likeliest outlets for a second goal and showed an admirable attitude - something that may have been missing under former boss Ole Gunnar Solskjaer.
James Ward-Prowse's claim for a place in the England squad continues to increase after he provided two assists in Southampton's win at Tottenham in the week.
The Saints stalwart is a notable threat with his set-piece delivery, as well as he ability from attacking free-kick positions as Man. Utd know all too well after scoring against them last season.
Manchester United continue to be without both Fred and Alex Telles after the Brazilian duo tested positive for Covid-19 earlier in the week. Eric Bailly continues to be a doubt, with Cristiano Ronaldo likely to return to the starting line-up having been a substitute at Burnley.
Southampton, meanwhile, remain without Lyanco and goalkeeper Alex McCarthy - both of whom have muscle injuries. The game at Old Trafford could come too soon for Nathan Tella, who with a groin injury has missed the last three games.
Man. United: 4-2-3-1: De Gea; Dalot, Varane, Maguire, Shaw; Pogba, McTominay; Rashford, Fernandes, Sancho; Ronaldo.
Southampton: 4-2-2-2: Forster; Walker-Peters, Bednarek, Salisu, Perraud; Ward-Prowse, Romeu; S. Armstrong, Walcott; Broja, A. Armstrong.
Saints will need little reminder of their last trip to Old Trafford – an infamous 9-0 loss back in February 2021 – and will be determined to turn up the pressure on their underperforming hosts.
Things got off to the worst possible start for Ralph Hasenhuttl's side that night when Alexandre Jankewitz was sent off two minutes into his full Premier League debut.
Earlier this season, though, was a different story at St. Mary's Stadium. Fred scored an own goal to give Southampton a first half lead, which was cancelled out by Mason Greenwood in the second half as the teams played out an entertaining 1-1 draw.
How to watch
The match at Old Trafford will be broadcast live on BT Sport, with kick off at 12:30pm and highlights available shortly after the full time whistle on Sky Sports YouTube channel.