United came from behind early on in the game, but the Cottagers will feel hard done by after matching their opponents for most of the game.
Fulham brought veteran goalkeeper Mark Crossley back into the side at the expense of loan star Tony Wanrer, while Collins John was given a starting spot upfront.
The most eye-catching changes came from Sir Alex Ferguson, who changed to 4-4-2 formation. It was a shape which United fans have been desperate to see, but it meant that Paul Scholes was left on the bench.
United fans travelled down with optimism, but that soon turned to despair as Fulham grabbed the lead within two minutes.
Brian McBride flicked the ball towards his strike partner John, and the Dutch Under-21 International outmuscled Rio Ferdinand before firing past Edwin Van der Sar.
It was the perfect start for Chris Coleman's men and set up a roaring first half.
John was then denied by a last-ditch challenge from Kieran Richardson before United took control. Wayne Rooney and Ji-Sung Park were looking dangerous and on 17 minutes the South Korean was brought down in the penalty area by right-back Moritz Volz.
The referee pointed straight to the spot and van Nistelrooy converted the perfect spot-kick into the bottom corner of the net past the despairing Crossley.
Two minutes later United took the lead when Park picked out Rooney with a perfect pass and the England striker coolly tucked his shot away.
United looked dangerous with every attack, but handed Fulham a 22nd minute equaliser after Scotland international midfielder Darren Fletcher brought down Luis Boa Morte.
Claus Jensen played a teasing cross into the United box and as Ferdinand and Van der Sar hesitated the ball bounced into the far corner of the net.
Moments later Fulham almost took the lead, but Van der Sar made a good stop from a stinging Steed Malbranque volley.
On the stroke of half-time, United grabbed their third. Park raced down the right as Fulham appealed for offside, he set up van Nistelrooy for a simple tap-in.
After half-time, Rooney missed the target when he should have scored, and Papa Bouba Diop almost hit the net for Fulham with a rasping drive on 58 minutes.
Almost immediately United had to replace the injured Richardson with Phil Bardsley, before Diop was wide with an effort from long range.
Diop was booked soon after for a foul on Park, while skipper Boa Morte had also been yellow-carded a few minutes earlier for a challenge on Rooney.
United held out, although Heidar Helguson had a late chance to snatch a point when he headed over the crossbar from close range, following a pinpoint cross from fellow sub Tomasz Radzinski.
Man of the Match: Ji-Sung Park - The Korean wing-back gave an all-action display for United, setting up two goals and also winning the penalty from which his equalised Fulham's opener.