Goals from Alen Boksic, Szilard Nemeth and Joseph-Desire Job condemned United to their second straight defeat.
Ryan Giggs pulled one back for the visitors with his 60th-minute strike.
Although United remained in third place with 35 points from 20 games, they are seven points adrift of leaders Arsenal and only one ahead of fourth placed Everton.
The win lifted Middlesbrough two places up to eighth on 29 points.
This was the third time in two seasons that Middlesbrough manager Steve McClaren, the former number two at Old Trafford, had come out on top against his old boss Alex Ferguson.
Manchester United captain Roy Keane made his first start since August 31 at the Riverside but he struggled to have an influence on the proceedings.
Fine finishes by Croatian Boksic and Slovakian Nemeth either side of halftime put Middlesbrough into a deserved 2-0
Ryan Giggs's close range effort on the hour gave United hope but five minutes from time Job killed off the visitors, who also lost at Blackburn on Sunday having won their previous eight games.
Middlesbrough took the lead just before the break when Boksic fired in his second goal of the season.
Nemeth doubled the scoreline three minutes after the interval as he burst through on the right to give United goalkeeper Fabien Barthez no chance.
Manchester United hit back on the hour after Middlesbrough's defence failed to cut out a right wing cross from Ole Gunnar Solskjaer and Giggs had an easy task to score from close range.
Ferguson sent on David Beckham and Rio Ferdinand in a bid to pull the game round but Middlesbrough made certain of the points five minutes from time.
Substitute Massimo Maccarone had been on the field for only two minutes when he headed a Geremi cross into the path of goalscorer Job.
© 2025