Dimitar Berbatov opened the scoring in the 12th minute with his 22nd goal of the season before Antonio Valencia made it 2-0 as United opened up a 10-point lead at the top of the table after an eighth win in 11 league games.
It capped a bitter-sweet day for United manager Sir Alex Ferguson after his horse, What A Friend, failed to finish the Grant National, which was taking place at the same time as this game.
With Wayne Rooney serving a two-match suspension for his expletive-laden tirade at West Ham, Berbatov started on his own in attack as Ferguson had one eye on Tuesday's Champions League quarter-final with Chelsea.
In total, the United manager made eight changes to the side that earned a 1-0 first leg lead at Stamford Bridge in midweek.
Rio Ferdinand was not involved in the 16 while keeper Edwin van der Sar, Javier Hernandez and Michael Carrick were among the substitutes.
Fulham has lost on all seven visits to Old Trafford since their last victory at the venue in 2003, but the mid-table visitors quickly settled as they twice tested United's stand-in keeper Tomasz Kuszczak in the opening exchanges.
The Polish stopper kept out Gael Kakuta's 20-yard drive in the opening minute before Kuszczak made an even smarter save to deny Moussa Dembele in the sixth minute.
United had not had an effort on goal when Bobby Zamora was presented with a great opportunity to give Fulham the lead after the ball deflected into his path inside the United penalty area.
However, the England international was unable to keep his composure and lashed the eighth minute effort high and wide when he should have at least tested the keeper.
It was to prove a costly miss. Four minutes later United were ahead as Berbatov demonstrated why he is the Premier League's top scorer.
There was certainly a touch of good fortune as replays showed the striker may have been off side, but there was no disputing the fact that Berbatov finished well from eight-yards after collecting a pass from the lively Nani.
United failed to scale the heights of their midweek European success yet, with their noses in front, they rarely looked like allowing Fulham back in.
Indeed, Ferguson's side doubled their adavantage before half time as Fulham's bright early opening became a distant memory.
Anderson had already spurned a 19th minute opportunity to make it 2-0 when the Brazilian screwed a 16-yard attempt hopelessly wide after the visitors defence had been sliced wide open.
Fortunately for United, fellow South American Valencia was not so wasteful in the 32nd minute.
The 25-year-old, who has recently returned to action after recovering from a broken ankle, was presented with the simplest of headers two yards from goal after Nani's attempted finish from an acute angle was deflected by Fulham defender Aaron Hughes.
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