The hosts go into the match languishing in the relegation zone, while United are seventh in the table and already 14 points adrift of leaders Manchester City.
The bookmakers have Hughes as the favourite to be the next Premier League manager to leave his post - marginally ahead of his opposite number this weekend - and while defeat to Manchester United may not seal his fate, it would surely edge him closer towards the exit door.
The former United striker has won just three of his 21 league games in charge of the Saints, just about doing enough to stave off the threat of relegation last season but plunging the team straight back into trouble this term.
Indeed, many other clubs may have already pulled the trigger, particularly following last weekend's 3-2 defeat to fellow strugglers Fulham which ensured that only goal difference is currently keeping Southampton off the bottom of the table.
Since that see-saw thriller at Craven Cottage Southampton have also been eliminated from the EFL Cup courtesy of a midweek penalty shootout defeat to Leicester City in their rearranged fourth-round fixture.
The Saints therefore come into Saturday's match without a win inside normal time from their last 11 outings across all competitions, stretching back to their 2-0 victory at Crystal Palace on September 1.
That victory at Selhurst Park remains Southampton's solitary league win of the season, and one of the main concerns nested in that statistic is that Hughes's side remain winless in front of their own fans this term.
Indeed, the Saints are currently enduring their longest ever wait for a home league win from the start of a season while being one of only two teams yet to pick up a home victory this term, and their poor form at St Mary's now stretches back a full year.
The first home game of December 2017 began a run of just one win in their last 17 league outings at St Mary's, with that coming against Bournemouth in April.
Half of Southampton's points this season have still come on their own turf, but Hughes will be acutely aware that it is a points tally which could be significantly better had his side been able to hold on to leads.
The south coast outfit have dropped more points than any other team so far in 2018-19, taking the lead on five occasions but going on to win just one of those - not an ideal record going into a game against a United side that has made a habit of coming from behind in recent weeks.
Hughes will likely need to pull off a few shocks and upset the odds at some stage over the coming weeks if he is to keep his job, though, with three of his side's next four games coming against members of last season's top six.
Recent Premier League form: LDDLDL
Recent form (all competitions): DDLDLL
Jose Mourinho's furious eruption of emotion at Marouane Fellaini's late winner against Young Boys in midweek demonstrated a mix of frustration, relief and perhaps even vindication.
The United boss certainly took the opportunity to talk up his achievements in the post-match press conference, but despite his repeated insistence that his record remains special there is no doubt that the aura around both Mourinho and United has further deteriorated this season.
Fellaini has long been an effective Plan B for United, but the Red Devils should not have had to rely on the Belgian - and a stunning David de Gea save - to see off a Young Boys team missing a host of their best players at Old Trafford.
Even the victory - and the passage through to the last 16 which it secured - is not enough to paper over the cracks of what was another uninspiring performance from the 20-time champions of England, which came just three days after a goalless draw with Crystal Palace.
United could have easily lost that game to the Eagles, but the stalemate means that only this weekend's opponents have recorded more 0-0 draws than United's tally of 10 since Mourinho took charge at Old Trafford.
It is a damning statistic for a club of United's size and attacking heritage - particularly considering the talent they have at their disposal in the final third - and they will go into this weekend's match having scored the joint-fewest goals in the top eight of the table.
The result against Palace did at least hand them their first clean sheet in eight league games and just their second of the season, but they simply must improve at both ends of the field if they are to bridge what is now a seven-point gap to the Champions League places, having registered a negative goal difference after 13 games of a top-flight campaign for the first time since 1977-78.
Any lingering hopes of a title challenge were effectively ended by the derby defeat to Manchester City before the international break, and United now find themselves closer to bottom-of-the-table Fulham than they are to their local rivals at the top.
However, Mourinho has vowed to take United back into the top four before the end of the year, and despite patchy form which has seen his side win five, draw four and lose four of their last 13 games, they will still be favourites to overcome a struggling Southampton team this weekend.
Previous trends this season suggest that United may have to do it the hard way, though; they have conceded a joint-league high five goals in the opening 15 minutes of games in 2018-19, but have come from behind to beat Southampton on eight occasions in the Premier League - a joint-high in the competition.
However, should United suffer defeat then they would equal their club record of seven Premier League away losses in a calendar year and further questions will surely be raised over Mourinho's future ahead of Wednesday's trip to face Arsenal at the Emirates Stadium.
Recent Premier League form: WDWWLD
Recent form (all competitions): WWWLDW
Alexis Sanchez picked up a hamstring injury in training on Thursday and is a doubt for this match, although he was an unlikely starter anyway after being left out of the squad entirely for the midweek win over Young Boys.
Mourinho also notably left Paul Pogba and Romelu Lukaku out of his starting lineup for that game, but both were called off the bench and contributed to the eventual victory so are expected to be brought back into the team on Saturday.
Lukaku is now 11 games without a goal for the Red Devils, although he has scored four goals at St Mary's in the Premier League - only Olivier Giroud and Robin van Persie have ever netted more at the stadium as visiting players.
Anthony Martial has stepped up during Lukaku's drought, scoring four of United's last five Premier League away goals, with only Harry Kane and Pierre-Emerick Aubameyang having registered more on the road this season.
Victor Lindelof remains sidelined which means that Phil Jones is likely to partner Chris Smalling once again, while Luke Shaw should return from his domestic suspension and Ashley Young is expected to come in for Antonio Valencia.
Southampton possible starting lineup:
McCarthy; Cedric, Yoshida, Hoedt, Targett; Lemina, Hojbjerg; Ward-Prowse, Armstrong, Redmond; Austin
Man Utd possible starting lineup:
De Gea; Young, Smalling, Jones, Shaw; Fellaini, Matic, Pogba; Lingard, Lukaku, Martial
Head To Head
United are unbeaten in their last five meetings with Southampton across all competitions, but there has been just one goal in the last three league editions of this fixture - a Lukaku winner at St Mary's last season.
The Saints have managed two wins in their last eight meetings with United - as many as in their previous 22 before that - but both of those victories came at Old Trafford.
Southampton have not won at home to United since a 1-0 victory in August 2003, when James Beattie scored the only goal of the game in the 88th minute.
We say: Southampton 0-1 Manchester United
Nothing we have seen from these two sides so far this season suggests that this will be a thriller. Both managers and both clubs desperately need a win to lift their spirits, but Southampton are in dire form at the moment and United should have enough to scrape another victory.