Sheffield United pulled off one of the shocks of the season as title-chasing Manchester United were beaten 2-1 by Chris Wilder's improving side.
Ole Gunnar Solskjaer's side had the chance to leapfrog Manchester City back into top spot but froze under the pressure against bottom-of-the-league Blades, who had only won once in the Premier League this season.
Kean Bryan headed home the opener when taking advantage of some questionable goalkeeping from David de Gea but former Sheffield United man Harry Maguire scored his first goal at Old Trafford to level it up.
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A late siege on the Sheffield United goal was expected but Chris Wilder's substitution to bring on Oliver Burke paid off as he struck the winner via a big deflection off Axel Tuanzebe.
The result leaves Manchester United a point behind City, who have a game in hand, while the great escape could be on for Wilder's boys. They are 10 points from safety.
Man Utd De Gea (4), Wan-Bissaka (5), Maguire (6), Tuanzebe (5), Telles (6), Pogba (5), Fernandes (5), Matic (5), Martial (4), Rashford (5), Greenwood (5)
Subs: Cavani (5), Van De Beek (N/A), Shaw (N/A)
Sheff Utd: Ramsdale (8), Basham (9), Jagielka (9), Ampadu (8), Baldock (7), Lundstram (7), Norwood (7), Fleck (9), Bryan (7), McGoldrick (8), Sharp (7)
Subs: Burke (8), Bogle (7)
Man of the Match: Phil Jagielka
How Man Utd were stifled by wonderous Wilder...
Having beaten Liverpool in Sunday's FA Cup encounter, there was a feeling that United would be firing on all cylinders but they played without tempo and were punished.
Bryan got the Blades off the mark from a corner as Billy Sharp's nudge on De Gea went unpunished midway through the first half. That was the visitors' second big chance of the evening as Sharp had already been denied one-on-one by De Gea but VAR may have stepped in with the striker looking borderline offside.
Even falling behind failed to trigger a Man Utd response. They dominated possession but against the compact Blades, they looked devoid of inspiration.
United thought they had equalised when Anthony Martial slotted into an empty net, but Maguire was adjudged to have fouled goalkeeper Aaron Ramsdale when challenging for the ball.
Mason Greenwood dragged wide after being put through by Bruno Fernandes early in the second half, but time after time it was Sheffield United winning the key battles.
David McGoldrick missed with an effort hit with the outside of his boot, then blazed over when one-on-one - unaware the offside flag would be raised.
An equaliser didn't look likely but Maguire powered home a header and immediately raced back to the halfway line as there only looked one winner from that point.
But just as Manchester United looked to be building momentum, the Blades caught them napping at the back.
United afforded Wilder's boys so much space in and around the box with Nemanja Matic and Martial ambling back into position. John Lundstram had time to pick out Burke, whose strike hit Tuanzebe - making his first league start of the season - and deflected past a helpless De Gea.
United had 16 minutes to put Sheffield United under some late pressure but their inability to break down the Blades low-block was a worrying sight. Only an Alex Telles looping shot really tested Ramsdale, who wasn't called upon to make any late saves as Wilder's side held on relatively comfortably.
This was a big reality check for Solskjaer's side.
Man of the match: Phil Jagielka
Can someone really peak at the age of 38? Well, Phil Jagielka put in a shift that belied his ageing limbs as he headed, kicked and cleared away everything Manchester United could throw at him on just his second start of the season. Jagielka was the oldest outfield player to start a Premier League match at Old Trafford against Manchester United since Richard Gough in February 2001 for Everton (38y 304d).
He made a match-high six clearances and was always in the right position, showing an ability to read the game never leaves you.
Of course, there will be huge questions, and probably more than a tinge of embarrassment, regarding how a team supposedly capable of winning the Premier League couldn't find a way past a player that started playing professional footballer before United striker Mason Greenwood was even born.
What the managers said
Ole Gunnar Solskjaer said: "We had all the possession but when you concede two bad goals it's always going to be difficult. We didn't create big enough chances to score enough goals.
"That magic was missing, that little bit extra. They defended well, fair play to them but we didn't have the right ideas or solutions.
"It wasn't to be, the second goal we conceded is so poor, so sloppy. Easy. We stopped getting out to the ball, three or four bad decisions which is out of character.
"There will be no big inquest. There have been so many odd results this season but with the world as it is we have been the most consistent team, it hit us today."
- Manchester United have lost four of their 10 Premier League home games this season, their most in a single campaign since 2013-14 under David Moyes (6) and Ryan Giggs (1).
- Manchester United have lost two of their last four Premier League home games against the side starting the day bottom of the table, one more loss than in their other 21 such matches in the competition (W16 D4 L1).
- Since 2003-04, Sheffield United are just the fourth side to have as few as five shots in a Premier League game at Old Trafford against Man Utd and win, after Burnley (January 2020), Crystal Palace (August 2019) and Swansea (August 2014) - all in the post-Sir Alex Ferguson era.
- Since the start of last season, no Premier League side has conceded more league goals from corner situations than Manchester United (14, level with Brighton & Chelsea).
Manchester United have a chance to get back to winning ways when travelling to Arsenal on Saturday, a game live on Sky Sports. Meanwhile, the schedule doesn't get any easier for Wilder as his side face a trip to play Manchester City on Saturday at 3pm, also live on Sky Sports.