The striker controlled a shot from Yohan Cabaye before turning and rifling the ball past Fulham goalkeeper Mark Schwarzer.
Newcastle had earlier hit the woodwork three times, but were indebted to their own keeper Tim Krul, who made two outstanding saves.
The Magpies were keen to make the most of home advantage early on, but it was Fulham who had the first real chance of the game after four minutes when Dimitar Berbatov’s deft shot with the outside of his right foot floated a few inches over Krul’s crossbar.
The pattern of Newcastle failing to make the most of their possession, and Fulham looking hungry when on the attack, was set for most of the half, and the hosts were forced to make an early change when Davide Santon limped off with what looked to be a pulled hamstring on 17 minutes.
Cisse was Newcastle’s most potent weapon, curling a delicate effort just around the post and seeing Brede Hangeland get in the way of a fierce shot within a couple of minutes of each other.
But the Senegalese also wasted a chance to set up Sylvain Marveaux, shooting wide when a pass to his team-mate would have been the better option.
Fulham grew in confidence and were only denied by a moment of brilliance from Krul, who threw himself in front of Stanislav Manolev’s shot from point-blank range at a corner.
Newcastle went into their shells late in the first half, but they were much more urgent after the break and were denied by the woodwork on 52 minutes when Vurnon Anita, Santon’s first-half replacement, saw his shot take a big deflection that wrong-footed Schwarzer completely but bounced off the top of the Fulham crossbar.
And 10 minutes later the home side hit an upright twice within seconds. Yoan Gouffran’s header bounced up and off Sascha Riether onto the post, and Cisse’s follow-up shot did likewise, although replays suggested that the Fulham full-back’s deflection may have been off his arm.
Krul then kept Berbatov at bay with another superb save, arching to his left to tip the Bulgarian’s header over his bar.
Steven Taylor and Cisse tested Schwarzer low down at either post at the other end, and substitute Shola Ameobi was a nuisance to the Fulham defence from the moment Newcastle manager Alan Pardew threw the striker on for his customary cameo appearance.
But Fulham’s hopes of hanging on for a point were dashed deep into stoppage-time by a moment of skill from Cisse. As the ball was drilled back into the box by Cabaye, Cisse took the pace off it enough to spin round and shoot beyond the despairing Schwarzer.
The striker’s celebrations with the crowd earned him a booking but the three points that were confirmed seconds later will have eased some of Newcastle’s relegation worries, while Fulham are still just short of the 40-point barrier.