Mauricio Pellegrino, appointed boss of Saturday's hosts in the summer, as struggled to win over the early criticisers having failed to hit the net in four of the club's six outings across all competitions this term, and will definitely face a difficult task as the Red Devils are the visitors.
José Mourinho and Manchester United are surely solidifying why so many had tipped them for the title prior to a ball being kicked as they sit second in the Premier League only in alphabetical order with fierce rivals City leading the table.
The Saints will more than likely going to be underdogs going into the fixture but Pellegrino could be determined to make home turf a fortress, making it an endurable match-up for Manchester United.
One return for Saints, another major absentee from United
Southampton have frustratingly lacked a goal scoring touch this season, however, the team could be handed a significant boost as star man Virgil van Dijk could return to the first-team picture and earn his first start since January - he accumulated minutes during the club's under-23 game earlier this week.
In terms of attacking options, Shane Long is very much up to the challenge to become Pellegrino's first choice striker after being such in the victory over Crystal Palace last weekend.
Whilst Romelu Lukaku has rightfully been given all the credentials for Manchester United's impressive start to the campaign, Paul Pogba will remain on the sidelines for the foreseeable future due to the injury he picked up in his side's Champions League triumph against FC Basel.
Meanwhile, in the defensive side it is Luke Shaw who could feature in the game with his former employer - the prosperous left-back was a substitute in the midweek win over Burton Albion, so is heavily likely to be within the matchday squad for the trip to Hampshire.
Stalemate in previous St. Mary's meeting
It has only been a measly four months since these two progressive clubs last locked horns. In the penultimate set of Premier League fixtures of last season, Southampton were eager to finish on a high in what was a disappointing campaign for the Saints. Whereas United also had the same hopes despite winning the Europa League.
José Mourinho played out a somewhat experimental team which included teenager Axel Tuanzebe; Scott McTimonay and Demetri Mitchell were amongst the bench.
Southampton were able to hold out to a goalless draw but held the record for the second worst conversion home rate in the top-flight, only Sunderland were able to boast about a more damaging figure.
Experienced and servant midfielder Michael Carrick was brought out to make his 700th career appearance.
Are Manchester United the keen favourites prior to kick-off?
Form would certainly side with Manchester United being favourites and, on paper, it surely looks the case with their unbeaten record in all competitions up this point.
The ability to rotate their squad so much for the comfortable triumph over Burton Albion in the Carabao Cup means a number of key players, including Lukaku, are fresh going into the encounter with Mauricio Pellegrino's Southampton.
However, the Saints should be full of confidence after the satisfying three points against bottom-of-the-table Crystal Palace, where Steven Davis bagged the only goal on his 200th Southampton match.