A second successive defeat for Sir Alex Ferguson's side was on the cards as early as the 17th minute when Paul Scholes was dismissed for handling Bobby Zamora's goal-bound effort on the line, with Danny Murphy stepping up to slam home the penalty.
And despite the visitors piling on the pressure in the second half, their fate was sealed when Zoltan Gera fired home from close range with just three minutes left, before Wayne Rooney was sensationally red carded with a minute remaining for hurling the ball at referee Phil Dowd.
Fulham hadn't beaten United at Craven Cottage since 1964, but on the basis of the first half you would have thought they were the title-chasing side. The hosts utterly dominated the opening 45 minutes as they tore into the visitors from the opening whistle.
The reigning Premier League and European champions were rattled and became careless in possession as Fulham put their midfielders under pressure at the earliest possible opportunity.
And Fulham got their reward for such an enterprising start when they took the lead - and saw United suffer the double-whammy of having a player dismissed.
Scholes - who had started terribly - was the man to go, and he could have little complaint as he clearly blocked Zamora's goal-bound header on the line with both hands as the striker attempted to force home the rebound after his initial header had been saved.
And it was Murphy - a former Liverpool player who had scored the winner against United on three previous occasions while at Anfield - who stepped up to confidently slam the penalty into the roof of the net.
The visitors were in disarray and only a combination of last-ditch blocks and wayward shooting stopped Zamora, Andy Johnson and Clint Dempsey from making it 2-0.
United were reduced to arguing with each other but, having made it to half-time without any further damage, they reorganised, with Rooney replacing the hopelessly ineffective Dimitar Berbatov.
The balance of the game was immediately altered, although the visitors' momentum was stunted when Cristiano Ronaldo lost his temper and launched into an ugly challenge on Murphy for which he was lucky just to get a yellow card.
There was no doubting who was on top now, with Mark Schwarzer making a miraculous close-range double save from Park Ji-Sung and Rooney when it seemed both were certain to score.
But the game was put to bed when Gera swivelled and acrobatically volleyed home Johnson's cross, before a terrible day for United - now just four points ahead of Chelsea and Liverpool - was sealed when Rooney received his second yellow card for hurling the ball at Dowd in a fit of pique.