The Blades have picked up just one point from their opening 12 games - the worst start in Premier League history - and welcome a side with a flawless away record so far this season.
When these two sides last met in one of the first matches after lockdown it was a showdown between two Champions League hopefuls.
For Sheffield United at least, that could not be further from the truth now as they find themselves struck with a serious case of second-season syndrome.
Manchester United have not had things all their own way either this term but, despite sitting in the relatively lowly position of eighth, they are at least still in the hunt and sit just five points off the top of the table with a game in hand.
Ole Gunnar Solskjaer's side have their away form to thank for that, with 15 of their 20 points coming on their travels.
The stats behind Man United's away form are remarkable; victory on Thursday would see them become only the fourth side in English top-flight history to win 10 consecutive away league games, while they could also become the first team to score two or more goals in 10 successive top-flight games since Tottenham Hotspur more than 60 years ago.
The Red Devils have had to do that in order to win games, though, incredibly conceding the first goal in all five of their away matches so far before coming back to win - no team has ever done that in six away games during an entire Premier League season.
Quite how Man United can be stringing together one of the best runs of its type in English football history away from home yet be so poor at Old Trafford will baffle Solskjaer, but he will know that if he can begin to emulate this away form on their own patch then they could very quickly climb up a congested table.
It is now 12 away league games without defeat stretching back to last January, and on paper this looks like the perfect fixture for them to extend both that run and their winning streak further.
Whereas Man United's away form is among the best in top-flight history, Sheffield United's form overall is among the worst, with only the Red Devils themselves - in 1930-31 - having picked up fewer than one point after 12 games of a campaign.
Indeed, in the history of the top four tiers of English football only three other clubs have had one point or fewer at this stage of a season, so Sheffield United's start to the campaign is among the worst ever seen in this country, yet alone in the top flight.
It is quite a fall from grace for a side that punched above their weight in the Champions League race for much of last season and, while Chris Wilder will be keeping things in perspective following a meteoric rise to this level, it is getting increasingly difficult to see them overcoming such a wretched start.
Positive results for Burnley and Fulham at the weekend mean that the gap to safety is now eight points, which at their current rate of form would take them another 96 games to bridge.
It is not just this season either; including the end of last term, Sheffield United have lost 14 and won none of their last 15 Premier League games and six of their last seven at home - as many defeats as they had suffered in their previous 30 at Bramall Lane.
Another defeat on Thursday would see them lose four home games on the bounce for the first time since April 1965 and also lose more than seven home games in a single calendar year for the first time since 1975.
Sunday's 3-0 loss at Southampton saw them attempt just 74 passes in the first half - the fewest by a Premier League team since February 2007 - and with a league-low five goals to their names too it is difficult to see quite how they can escape from the mire any time soon.
Sheffield United Premier League form: LLLLLL
Manchester United Premier League form: LWWWWD
Manchester United form (all competitions): WWLWLD
Edinson Cavani remains a major doubt for this match after once again missing out in the Manchester derby, with Solskjaer admitting that he does not expected to have the Uruguayan available.
Anthony Martial was only deemed fit enough for the bench in the derby but could come back into the starting XI for this match in place of Paul Pogba, whose agent has once again been in the news regarding the midfielder's future.
Alex Telles could also come back into the side after sitting out at the weekend, but otherwise changes could be kept to a minimum, which means that Dean Henderson may again be limited to a watching brief against his former club.
Bruno Fernandes should start again as he looks to improve his tally of four goals and four assists in four Premier League games against teams starting the day in the relegation zone.
The Portuguese playmaker has directly contributed to a goal in 11 of his 12 Premier League away games so far, netting 11 times and creating six more.
Sheffield United possible starting lineup:
Ramsdale; Basham, Egan, Stevens; Baldock, Berge, Ampadu, Fleck, Lowe; Mousset, Burke
Manchester United possible starting lineup:
De Gea; Wan-Bissaka, Lindelof, Maguire, Telles; McTominay, Fred; Mata, Fernandes, Rashford; Martial
We say: Sheffield United 0-2 Manchester United
Everything points to a Manchester United win in this match as the league's worst home record takes on the best away record.
The Red Devils' form on the road in the league is remarkable considering the lack of consistency elsewhere and it will surely only be a matter of time before their winning run ends, but it is difficult to see that happening at the home of a team which is on course to go down as one of the worst in top-flight history.
Top betting tip
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