Palace looked to have come away from the north east with a second successive point in the space of two weeks following their stalemate at Sunderland.
But with time running out Hatem Ben Arfa found Cisse with a delightful cross and the Senegal international headed past Julian Speroni for the winner.
It was only his second Premier League goal of the season and his first from open play in a year.
Midfielder Cheick Tiote had rattled the crossbar seconds earlier as Palace looked to have survived, but Cisse ensured the Eagles remain firmly entrenched in the battle for survival.
Speroni’s heroics had kept the Eagles in a game of little real quality until that point, and they might even have been ahead themselves with Yannick Bolasie clipping the crossbar seconds after Kagisho Dikgacoi had gone one-on-one with keeper Tim Krul.
With Alan Pardew watching the game via video-link from the club’s training ground and owner Mike Ashley making a rare appearance in the stands, it was assistant manager John Carver who took centre stage once again, and he headed for the dressing room at the break a frustrated man.
Newcastle largely dominated the opening 45 minutes as Palace receded in numbers in an attempt to deny the hosts time and space, and the ploy proved effective for much of the first half.
Cisse was denied by a fine 12th-minute reaction save from Speroni after leaving defender Adrian Mariappa on his backside and thumping in a left-foot shot, with Luuk de Jong heading the rebound over.
The Senegal striker, who started the game with only one league goal to his name this season, looked certain to add to his tally when he met Mapou Yanga-Mbiwa’s inviting 32nd-minute cross with a deft touch, but Speroni was once again equal to the task.
Full-back Paul Dummett came as close as anyone to opening the scoring, but his injury-time free-kick whistled inches over the crossbar.
For their part, Palace attempted to hit Newcastle on the break with the muscular Cameron Jerome causing all kinds of problems for central defensive pairing Fabricio Coloccini and Mike Williamson.
He headed an early Jason Puncheon shot wide and saw a 24th-minute shot blocked by Speroni, but it was midfielder Bolasie who almost blasted the visitors into the lead five minutes before the break when his rising left-foot drive only just cleared the bar.
The Eagles returned in much more positive fashion and went close twice within seconds when Puncheon smashed a blistering left-foot effort wide of the far post and Jerome saw another effort blocked by Yanga-Mbiwa.
With the game opening up, Palace were posing a more regular threat and Krul was called upon for the first time to block Dikgacoi’s shot as he ran on to Puncheon’s through-ball.
However, the Holland international needed the help of the crossbar seconds later when Bolasie sent in a curling shot from the left side of the penalty area.
It was then that Carver turned to Ben Arfa in the search for fresh inspiration, although it was Moussa Sissoko who fashioned a 62nd-minute opening for Cisse with a powerful run and cross, only for the striker to miskick.
Speroni kept Cisse at bay once again two minutes later with a crucial block after he had pounced on Sissoko’s pass, and the striker powered a 70th-minute header just over from Ben Arfa’s cross.
Tiote thumped a long-rage 92nd-minute effort against the bar with Cisse failing to turn home Yanga-Mbiwa’s cross from the rebound, but he made no mistake when Ben Arfa picked out his run at the death.