Clint Dempsey scored a hat-trick as Fulham stunned Newcastle in an extraordinary game at Craven Cottage.
Danny Guthrie's emphatic strike put Newcastle ahead, before Danny Murphy's penalty kick-started Fulham's comeback.
Dempsey bundled in his first and then finished off a blistering counter-attack before Bobby Zamora scored another penalty to make it 4-1.
Hatem Ben Arfa's individual effort gave Newcastle hope but Dempsey secured the points with a fine run and finish.
This remarkable match was always likely to hinge on how well Newcastle would cope without their Africa Cup of Nations stars - namely Cheick Tiote and Demba Ba - both of whom have been fundamental to the Magpies' successful campaign.
And, judging by their superiority throughout the first 45 minutes, it was a test they seemed well equipped to handle.
Ben Arfa, handed a start in the absence of Ba, featured on the right side of a front three that also contained Shola Ameobi and Leon Best, and the Frenchman was central to Newcastle's numerous first-half attacks.
The Magpies should have gone ahead when Fabricio Coloccini waltzed into the box unmarked, but then only managed to stab his effort straight at keeper David Stockdale from point-blank range.
It was a big miss that was forgotten moments later when Newcastle finally made their dominance count through Guthrie's long-range opener.
After collecting a pass from Ben Arfa, who had robbed Bryan Ruiz of the ball in the Fulham half, Guthrie rifled a thunderous left-footed shot past the outstretched Stockdale - a strike that sent the travelling support at the Putney End of the stadium wild with delight.
The error summed up Fulham's abject first-half performance. But the home side were handed a lifeline at the start of the second half when former Magpie Damien Duff was clumsily shoved in the back by full-back Davide Santon as he ran on to a long ball.
Santon, who was already on a yellow card, was lucky to escape further punishment before Murphy sent Dutch keeper Tim Krul the wrong way with the resulting penalty.
The goal ignited Fulham and suddenly the west Londoners looked the more likely to get a second. Zamora was denied by Krul, who smothered the England striker's attempt, before Chris Baird lashed the rebound just over the bar.
With Newcastle eager to re-establish their lead, they were found outnumbered at the back as substitute Andrew Johnson led a pacy counter-attack.
With Zamora to his right, Johnson played in the England striker, whose shot was parried to Dempsey, who turned in from close range.
Fulham were in the ascendancy, exposing Newcastle with every attack and the American soon put daylight between the sides with Fulham's third.
Set free down the right by Zamora, Dempsey fired low into the bottom corner to make it 3-1.
Newcastle were shell-shocked and had no answer to Fulham's second-half onslaught. The home side's incessant pressure meant a fourth goal was never far away - and it came courtesy of another penalty.
Centre-back Mike Williamson was unable to stop Johnson driving into a shooting position before Krul brought down the former Crystal Palace striker.
Like Santon earlier in the game, the Newcastle keeper was lucky to escape with a yellow card. But the real punishment came when Zamora, watched by England coach Fabio Capello, hammered the penalty down the middle.
Ben Arfa closed the gap to two goals again when he cut in from the right and fired a low shot inside the near post.
But the afternoon belonged to Fulham, and particularly Dempsey, who darted between Williamson and Coloccini to latch on to Murphy's long ball and fire in the first Premier League hat-trick by an American.