Red Devils run out dominant winners as fine goals from the champions' strikers add gloss to a fine performance with United finding themselves three up at half time
United took a 3-0 lead to half-time thanks to and early goal from Welbeck followed by a header from Nani and a deflected shot from Giggs, but really turned on the style with their final two goals as Rooney and Berbatov finished with aplomb.
Manchester United made one change to the side that defeated QPR in west London on Sunday with Anders Lindegaard coming in to replace David de Gea.
Elsewhere, Rooney became the youngest ever player in the Premier League to make 300 appearances at the age of 26 years and 58 days, eclipsing Gareth Barry's record of 26 years and 247 days set in 2007.
Fulham were unchanged from their 2-0 victory over relegation strugglers Bolton on Saturday with Martin Jol keeping his faith in Andrew Johnson as the lone striker up front.
United were almost forced into an early change when Phil Jones, deployed at right-back, challenged with Clint Dempsey in the air and clashed heads with the American. He was off the pitch for some time before he eventually re-joined the action, and almost as soon as he did the away side were in the lead.
Patrice Evra fed the ball to Nani on the halfway line, and the Portuguese winger was allowed to run unchallenged to the byline before sending in a pass to an unmarked Welbeck to slot home, a soft goal for the hostts to concede so early in proceedings.
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The hosts almost got back level after 20 minutes as Bryan Ruiz played a neat one-two with Dempsey on the edge of the area before bearing down on goal, only to be thwarted by a fantastic last-ditch tackle from Phil Jones who sent the ball out for a corner.
It was to be the young defender’s last action of the match as he was substituted straight afterwards, though it wasn’t clear whether this was due to the block on Ruiz or if he was still suffering the effects of the clash of heads with Dempsey earlier in the game.
It didn’t seem to phase United, who brought on Ashley Young in his place, and doubled their lead not long after.
A series of corners came United’s way, and they employed a number of short corner routines, with the final one resulting in a goal for Nani, who glanced a fantastically whipped ball from Giggs into the far corner.
United were extremely dominant, and it began to tell as Nani and Valencia were combining fantastically down the right wing, and it was this pairing that set up the third goal for United before half-time.
After Valencia intercepted a cross-field pass, United broke with speed and Nani found Giggs on the edge of the box who attempted to slot home, with Senderos sending his shot looping in over the top of the unfortunate Stockdale.
The hosts left the field to a chorus of boos from the fans, and it would take something very special to come back from such a heavy deficit against the reigning champions.
Fulham actually started the second half quite brightly, forcing three good efforts in the opening 10 minutes.
Lindegaard was forced into his first real stop of the match as he got down well to prevent a header creeping over the line, and a minute later Moussa Dembele went close, his shot drifting an effort just wide. John Arne Riise then saw a free-kick fade just wide after Murphy’s lay off.
Fulham were undoubtedly coming into the game, but faced a good blockade in the United defence who stayed strong until the end.
And in the final few minutes, Rooney capped his landmark peformance with a fine goal, as he was left in too much space far from goal and drove a fantastic effort in off the post that left Stockdale with no chance.
And minutes later, substitute Berbatov made it five, backheeling the ball into the far corner after a good break and cross from Valencia.
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