The Blades are eighth in the table heading into this clash with Southampton, who have gone six games without defeat to climb into 12th.
Finishing in the top four, or at least challenging for a Europa League spot, was a realistic possibility for United when the competition shut down for three months in March.
Chris Wilder's men were fifth in the table at that point, two points behind fourth-placed Chelsea and in front of the likes of Manchester United and Tottenham Hotspur.
Three wins in 10 post-lockdown has killed off those European aspirations, though, and United can now finish no higher than their current position of eighth on the final weekend.
Four defeats in their last eight matches, most recently losing back-to-back against Leicester City and Everton without scoring, is as many as they suffered in their previous 22.
Still, 2019-20 will long live in the memory of United supporters given that they were tipped by many to go straight back down following last year's promotion.
This season has hardly been a vintage one for opponents Southampton, although results and performances have at least picked up in the second half of the campaign and there is plenty of hope for the future.
The Saints' board deserve praise for sticking with boss Ralph Hasenhuttl on the back of October's 9-0 loss to Leicester City - a record home defeat in a top-flight fixture.
Hasenhuttl has now got his players playing the way he wants and Southampton have one of the best records in the division since football resumed in June.
In their eight matches since the three-month hiatus, the Saints have won four, drawn three and lost one in a run that includes a 1-0 win over dethroned champions Man City.
Last weekend's 2-0 victory over Bournemouth made it six games without defeat - Southampton's best run since August 2016 - and Hasenhuttl will now be looking to end the campaign on a high.
However, they have won just 18 of their 49 Premier League points in home games this season (37%). Only Crystal Palace have won a lower share of their points in a single campaign in the competition at home (33% in 1997-98).
Southampton have also won only one of their last nine final-day fixtures in the Premier League, losing five of those, so recent history is not exactly on their side.
Southampton's Premier League form: WWDDDW
Sheffield United's Premier League form: WDWWLL
Up top, Danny Ings looks certain to lead the line and is looking to become only the second Southampton player - after Matt Le Tissier in 1993-94 - to score 10 or more goals both home and away in a single Premier League campaign.
In terms of the visitors, Luke Freeman is Wilder's only confirmed absentee after picking up an injury against Newcastle United a little over a month ago.
Goalkeeper Dean Henderson has kept 13 clean sheets in the Premier League this season - only Bobby Mimms (19) and David Seaman (15) have kept more in their debut campaign in the competition among English goalkeepers.
Southampton possible starting lineup:
McCarthy; Walker-Peters, Stephens, Bednarek, Bertrand; Armstrong, Ward-Prowse, Romeu, Redmond; Ings, Long
Sheffield United possible starting lineup:
Henderson; Basham, Egan, O'Connell; Baldock, Berge, Norwood, Fleck, Stevens; McBurnie, McGoldrick
We say: Southampton 1-2 Sheffield United
While the Saints have improved, United have had by far the better campaign overall and we are backing them to pick up a 15th win of the season in this first meeting between the sides at St Mary's in any competition since February 2009.