Chris Wilder's men, fighting for their lives at the bottom of the table, surprisingly led twice at the Theatre of Dreams, with Jayden Bogle and Ben Brereton Diaz netting either side of half time.
After Wes Foderingham made a plethora of crucial saves in the first half, Brereton Diaz fired home his goal from close range five minutes after the interval to give the travelling Blades supporters hope of seeing their side end a nine-game winless run.
However, Harry Maguire — who scored an equaliser in the first half against his former club — won a penalty for Man United on the hour mark, and Bruno Fernandes stepped up to convert from 12 yards before contributing to another two goals in the closing stages to complete the turnaround.
Fernandes fired a stunning 25-yard strike into the top corner to put the Red Devils ahead with just nine minutes remaining, shortly before setting up Rasmus Hojlund to secure victory for the hosts, condemning the Blades to their 24th league defeat of the season.
Sheffield United make unwanted Premier League historySheffield United's spirited display at Old Trafford was ultimately in vain and they were made to rue more defensive errors as they cling onto their Premier League survival hopes by the finest of threads.
The Blades have now conceded four or more goals in eight Premier League games this season, more than any other team in the division.
In total, Wilder's side have shipped 92 goals across their 34 matches, the most ever conceded in a 38-game season in the competition, surpassing the previous record held by Derby County (89) in 2007-08.
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