The Red Devils travel to St Mary's on a three-game winning streak in all competitions, but they face a tough test against a Southampton side unbeaten in seven.
Fifth-placed Southampton enter this match sitting four points above United, albeit having played a game more than their opponents.
Not for the first time during his up-and-down tenure, Ole Gunnar Solskjaer has hit a good run of form just when it looked like his time at the club may well be up.
Solskjaer reportedly had one game to save his job on the back of defeats to Arsenal and Istanbul Basaksehir earlier this month. United have since won three from three.
Tuesday's emphatic 4-1 victory over Basaksehir ensures that, while not officially there yet, the Red Devils are in a very strong position to reach the Champions League last 16.
In the league, meanwhile, they have defeated Everton and West Bromwich Albion in their last two outings to climb into the top half on goal difference.
United were somewhat fortunate to see off a struggling West Brom side last weekend, though, requiring a retaken Bruno Fernandes penalty to get them over the line.
Solskjaer's men tend to perform better on their travels and they are seeking an eighth consecutive away top-flight win for the first time in their history.
In fact, record 20-time English champions United have only twice won four straight away games at the start of a league season - in 1913-14 and 1985-86.
Southampton are the side tasked with halting that run, and they too will be confident of coming away from this fixture with maximum points.
The Saints have won their last three home league matches by the same 2-0 scoreline and could win four in a row at St Mary's for the first time since May 2016.
Ralph Hasenhuttl has rightly earned plenty of praise for his work on the South Coast, with Southampton recently topping the table for the first time in 32 years.
Last week's 1-1 draw with Wolverhampton Wanderers saw them slip down to fifth, but this match presents another opportunity to show just how far they have come under the Austrian.
Southampton Premier League form: WDWWWD
Manchester United Premier League form: LWDLWW
Manchester United form (all competitions): WLLWWW
As for Southampton, Nathan Redmond has been ruled out because of a troublesome injury that has restricted him to three league starts all season.
Southampton possible starting lineup:
McCarthy; Walker-Peters, Bednarek, Vestergaard, Bertrand; Armstrong, Ward-Prowse, Romeu, Djenepo; Adams, Walcott
Manchester United possible starting lineup:
De Gea; Wan-Bissaka, Tuanzebe, Maguire, Telles; McTominay, Matic; Greenwood, Fernandes, Rashford; Cavani
We say: Southampton 1-1 Manchester United
Southampton have won three league matches in a row and are unbeaten in seven overall in a run spanning more than two months.
United are on the verge of setting a new club record of away wins, meanwhile, having won seven in a row on their travels in the top flight.
Factoring in the Red Devils' midweek exertions, with Southampton given nearly a full week off, we are tipping this one to finish level.
Top betting tip
Watch the Sports Mole Football Shorts prediction for this game below: