The Senegalese striker put the visitors ahead with a flick-volley combination that evoked memories of Thierry Henry and Matt Le Tissier before, halfway through 10 minutes of stoppage time, he unleashed an outrageous swerving volley from an acute angle that silenced Stamford Bridge.
The match was overshadowed by a potentially serious injury to Newcastle midfielder Cheick Tiote, who landed heavily after appearing to be elbowed by Chelsea's John Obi Mikel - Toon boss Alan Pardew later revealed that the Ivory Coast international was "fine", but there could still be retrospective action for Mikel.
Cisse, meanwhile, has 13 goals in his first 12 games for Newcastle, making him comfortably the most prolific top-flight striker per-minute this season.
It was also Newcastle’s first win at Chelsea since 1986, and one that put them four points ahead of the Blues with two matches remaining: Tottenham stay ahead of the Magpies on goal difference after their win at Bolton, the battle for fourth now between two rarities - Premier League clubs managed by Englishmen.
Chelsea had made six changes from the 6-1 win over QPR, with Saturday’s FA Cup final in mind, and they started as confidently.
But Toon, understandably cagey at the outset after their 4-0 hammering by Wigan, soon grew into the match.
The first real chance fell to the hosts, Daniel Sturridge mis-kicking following fine wing-play from Fernando Torres, but the visitors started to get Hatem Ben Arfa and Yohan Cabaye on the ball.
Their first opportunity was route-one though, as a high corner was flicked on by Mike Williamson at the far post, Demba Ba controlling expertly on his chest but ballooning the bicycle kick over.
Their second chance, however, was a work of beauty: a crisp passing move released Davide Santon wide left, the Italian full-back sending it low to Cisse who flicked the ball up with his first touch and buried an unstoppable volley into the top right with his second.
Chelsea did rally, Florent Malouda flashing a header wide after a wonderful cross by Torres; Branislav Ivanovic also went close, heading over from a Raul Meireles corner.
Going into the break the visitors fired a few more warning shots as, during a spell of good pressure, Petr Cech saved well from Ba, who then hit the crossbar from the edge of the box after a corner routine.
Chelsea started the second half positively, bringing on Juan Mata for the disappointing Sturridge, the Spaniard immediately involved as - after more wide work from Torres - he was denied a finish by a flying Tiote.
It was a brief interlude though as the match got scrappy, Roberto Di Matteo deciding to introduce Drogba during a lengthy interlude while Tiote was treated and carried off following a collision with Mikel.
There may be further repercussions for Mikel, who appeared to lead with the arm while rising with the Ivorian, possibly mindful of an earlier challenge where Tiote caught him with an elbow.
It happened right in front of referee Mark Halsey, who did not deem the challenge worthy of a free-kick, although how he failed to see it as a foul was a mystery to most.
Tiote may have done more damage landing than during the collision itself, his neck jarring as he hit the deck, but Mikel may well miss the FA Cup final if retrospective action is swiftly taken.
Play restarted a good nine minutes after the incident, and with Drogba in the fold Chelsea looked more threatening: he was denied a sure goal at the far post by an excellent intervention from Williamson, before hitting a few free-kicks off target.
Chelsea were piling it on, Cabaye accused of handball in the box before substitute Frank Lampard hammered an effort wide, but despite the pressure their final ball was poor, even Drogba making some poor decisions and touches.
They almost levelled through John Terry, whose flicked header from a Mata corner was cleared off the line in heroic fashion by Santon.
As the 90 minutes came up Krul was booked for his now customary piece of time wasting, although that was accompanied by the signalling of 10 minutes injury time on account of Tiote’s injury.
Midway through the additional minutes and Cisse struck again. Ironically it came as his side looked to wind down the clock - they had been aiming long throws upfield to gain territory and, having reached the deeper ends of Chelsea’s half, Shola Ameobi was just killing time when he flicked it to his strike partner.
But Cisse, as so often has been the case since his move from Germany this winter, had other ideas. With an almost lazy nonchalance, he flicked his right boot at the ball, sending it curling out and back in, up and down, over and around the floundering Cech and inside the top right - and all of this from the left wing.
Stamford Bridge was dumbfounded, Pardew seen exchanging shocked looks with Drogba as Ashley Cole - rested for the impressive Ryan Bertrand - gesticulated wildly to his fellow bench-warmers.
It was all most Chelsea fans needed to see, as the stands emptied to allow the away support a song and dance, both sides winding down the final minutes with disinterest as Newcastle effectively ended the Blues’ top-four hopes.