The 26-year-old Dutchman's goals proved vital for United on a day when they started and finished like champions, but showed too much sloppiness in between.
One penalty, one superb individual goal and a fine opportunist effort were the three components of the hat-trick in front of a crowd of 67,706 - a record for the Premiership.
Van Nistelrooy opened the scoring a minute before the interval.
As Ole Gunnar Solksjaer turned Martin Djetou in the box, he was unceremonesly up-ended by the Fulham player.
Referee Steve Bennett pointed to the spot and van Nistelrooy dispatched his right-foot penalty low to the right of diving Fulahm goalkeeper Maik Taylor and into the bottom corner of the net.
Van Nistelrooy's second goal after 68 minutes was pure magic.
He picked up the ball 10 yards inside the Fulham half, beat off the close attention of Sylvain Legwinski and, surrounded by three players, ran straight through the middle of the defence.
Taylor raced off his line only to see van Nistelrooy cleverly tap the ball around him from 12-yards and into the net.
With the game in the final minute, van Nistelrooy made it 3-0.
Paul Scholes found Ryan Giggs on the left and his cross into the centre of the Fulham box was met by van Nistelrooy - the left-foot volley from 6 yards going in off defender Jon Harley.
A United opening burst had seen van Nistelrooy twice thwarted by Taylor, while Giggs had a close-range shot cleared off the line by Andy Melville after Taylor failed to clear Solskjaer's effort.
But, as the half wore on, United relaxed and Fulham came more into the game with Louis Saha's vicious 20-yard drive rattling the bar.
The game went flat after the interval until van Nistelrooy's second goal.
However, his strike prompted a flurry of activity with United goalkeeper Fabien Barthez making a fine save to keep out Djetou's header and Taylor denying van Nistelrooy from 12 yards at the other end.