The Magpies conceded twice in the first-half at Craven Cottage, with Raul Jiménez's clinical finish opening the scoring inside five minutes before Emile Smith Rowe's strike doubled the hosts' advantage.
Harvey Barnes pulled a goal back for United within the opening minute of the restart, netting a third consecutive Premier League goal in as many matches, before Reiss Nelson's stoppage-time effort confirmed a first league defeat of the season for Eddie Howe's side.
Aiming to move into top spot of the Premier League with a victory against the Cottagers, Howe made four changes to the side which claimed a 2-1 win against Wolverhampton Wanderers on Sunday as Kieran Trippier, Lloyd Kelly, Joe Willock and Barnes were all handed starts in West London.
Joelinton looked to have fired United into an early lead as the Brazilian's rebound was fired into the net via the underside of the crossbar after his initial strike from Joe Willock's cutback was pushed away by Bernd Leno but the goal was disallowed after Willock strayed into an offside position.
Newcastle suffered a further blow barely a minute later as Jiménez netted for the hosts, with the Mexican striker controlling Adama Traore's cross with the chest and, after swivelling inside the box, slammed the ball into the bottom right-hand corner.
United almost fell further behind shortly after as Smith Rowe struck the crossbar for the Cottagers as the midfielder's bending effort from the edge of the box struck the woodwork.
Nick Pope prevented Jiménez doubling his and Fulham's goalscoring tally, with the England international standing tall to block the forward's shot from a tight angle. United were unable to clear their lines from the resulting corner, with the ball falling into Antonee Robinson's path but the American full-back slammed the ball wide of the target.
In the 22nd minute, though, Fulham extended their lead through Smith Rowe, who picked up Alex Iwobi's pass inside the box before quickly poking a low effort past Pope into the bottom right-hand corner.
Pope denied Traoré from netting Fulham's third goal of the afternoon after the Spanish winger dangerously drove into the box before his strike towards the near post was turned out by the left foot of the Magpies 'keeper.
Newcastle pulled a goal back within the opening 60 second of the restart through Barnes. Jacob Murphy, introduced from the restart, combined neatly with Isak before the substitute threaded a neat pass into Barnes' path, with the in-form forward calmly stroking the ball into the far right-hand corner.
Pope recorded a terrific save to deny Iwobi regaining Fulham's two-goal cushion, blocking the unmarked Nigerian's close-range volley from Traoré's lofted cross to the back post.
Bruno Guimarães, who scored the only goal in last season's Premier League away win against Fulham in April, exchanged passes with Joelinton before the Brazilian's attempt from the edge of the penalty area was fired over the crossbar.
The Magpies continued their pursuit for an equaliser as Anthony Gordon saw a low effort blocked by Leno before Murphy almost turned from provider to goalscorer as the winger's curling shot flew narrowly over the crossbar.
Fabian Schär went agonisingly close to netting his second goal in as many games as the Swiss centre-back intercepted Leno's intended pass to Smith Rowe but his strike smashed off the side-netting.
In the second minute of stoppage-time, Newcastle's hopes of avoiding defeat were distinguished as Nelson netted Fulham's third goal of the afternoon, intercepting Guimarães' misplaced pass before the Fulham substitute slotted the ball into the net.
