Fulham, though, have an impressive record at home and were looking to stretch their unbeaten run at Craven Cottage to seven games.
But it was the home side who had the better of the opening exchanges with Alexei Smertin, Simon Davies and Papa Bouba Diop all having coming close with shots from distance in the opening ten minutes.
Gary Neville was the surprise omission from the United line-up, Sir Alex Ferguson choosing Wes Brown to counter the aerial threat of Fulham.
United struggled to get into their stride and it was 15 minutes before Ryan Giggs had a shot, but his free-kick sailed straight into the arms of Jan Lastuvka in the Fulham goal.
It was no surprise then, when on 17 minutes the home side took the lead. Simon Davies chased a long ball over the top of the United defence which Edwin van der Sar and Nemanja Vidic combined to make an almighty hash of clearing.
The two collided on the edge of the box and the ball squirted clear to Brian McBride who, despite the best efforts of Rio Ferdinand on the line, was on hand to turn the ball against the far post and into the back of the net from a tight angle.
Van der Sar was even less convincing a minute later when he trod on a routine backpass before thumping the ball clear.
The goal sparked United into life as Ronaldo and Wayne Rooney came more in to the game and the visitors were back level on the half hour.
Rooney picked out an unmarked Giggs at the far post with a perfect ball and the Welshman volleyed the ball past Lastuvka with an excellent finish with the outside of his left boot.
United were now in full flow and missed a string of good chances to take the lead. Patrice Evra in particular should have done better when unmarked from 12 yards, but failed to get his shot on target.
Fulham were quickly out of the blocks for the second half with Davies forcing an excellent save from van der Sar when he controlled the ball well with his chest before spinning to hit a powerful volley goalwards.
Tomasz Radzinski came even closer minutes later only to be denied by the woodwork when he headed onto the crossbar at the far post.
Although United were always a threat, Fulham continued to dominate the game and Davies again missed a great chance to convert their superiority into goals, only to be denied by a brilliant stop fro the advancing Van der Sar when clean through.
Davies was alert to the rebound, but his looping header proved easy for the retreating Dutchman.
As Fulham failed to take their chances it was no surprise when United did.
Ronaldo was given the space to run down the right before snaking between Carlos Bocanegra and Smertin before tucking the ball away in the far corner to send the United fans behind the goal wild with celebration.
Fulham fought on and had a late penalty appeal turned down, but the three points belonged to United.