Cisse's sensational form since his January move to Newcastle hit new heights at Stamford Bridge as he produced one of the best goals ever seen at the ground, leaving Alan Pardew's men in what looks a straight shootout between themselves, Tottenham and Arsenal for third and fourth place.
The 26-year-old had already netted a stunning opener when he unleashed an outrageous 30-yard banana shot with the outside of his right foot that brought back memories of Roberto Carlos' free-kick for Brazil against France.
The goal was his 13th in 12 league appearances for Newcastle.
That came in 10 minutes of second-half stoppage-time added for a sickening head injury to Cheik Tiote, the only sour note on a night that left Newcastle four points clear of sixth-placed Chelsea with two games left to play.
The defeat was the first major setback for caretaker Blues boss Roberto Di Matteo in his bid to land the job full-time, with owner Roman Abramovich in attendance.
There is still plenty for Di Matteo to play for, starting with Saturday's FA Cup final, but the Italian's number one priority was qualifying for the Champions League and the Blues now look like they will need to beat Bayern Munich in next month's final to do so.
Despite insisting he would pick his strongest possible team tonight [Wednesday], Di Matteo rested both Juan Mata and Frank Lampard.
They certainly did not seem to miss them in an opening 10 minutes that threatened to be a re-run of Sunday's wet and muddy thrashing of QPR.
Fernando Torres looked in the mood to add to his first Blues hat-trick, although this time he failed to round the goalkeeper after being found by Raul Meireles' long ball.
The striker then bamboozled Tiote into an early booking before the Newcastle midfielder then left Ramires in some pain after accidentally kicking him in the hand.
Torres soon switched to assist mode, with Daniel Sturridge failing to connect with his low cross but that was as close as they went before the visitors got a grip.
And after Demba Ba hooked over under pressure, they struck in stunning fashion in the 19th minute.
Davide Santon and Cisse were both given too much space but the latter still needed just one touch to control the full-back's pass before volleying left-footed into the top corner.
A disjointed Chelsea took almost 20 minutes to muster a response as the absence of Lampard and Mata began to show.
When they finally did, they should have equalised, Florent Malouda heading Torres' brilliant cross wide and Branislav Ivanovic nodding Meireles' corner over under pressure.
But they were lucky not to go into the break two down when Demba Ba forced a scrambling save from Petr Cech and then drilled against the crossbar after Chelsea failed to deal with a corner.
Di Matteo wasted no time sending on Mata at the restart, with Sturridge withdrawn, something that almost had an instant impact when Tiote blocked Meireles' drive after more good work from Torres.
But the lack of precision in Chelsea's passing continued and they quickly resorted to trying their luck from set-pieces when Ramires went down very easily under Yohan Cabaye's challenge, earning the latter a booking.
Both teams were given the benefit of the doubt on the hour mark when Tiote's flailing arm caught the face of John Obi Mikel, who then led with his elbow in an aerial challenge with his fellow midfielder.
Tiote stayed down and it took around seven minutes to treat him and carry him off on a stretcher and in an oxygen mask with what looked a serious head injury.
Ryan Taylor came on, with Chelsea having already introduced Didier Drogba for Malouda, and tempers began to flare when Ba took exception an Ivanovic challenge from behind.
Newcastle were in danger of losing their composure and Ba was quickly withdrawn for Shola Ameobi, before Di Matteo threw on Lampard for Meireles in the 78th minute.
Chelsea's attacks became increasingly desperate and Lampard flashed wide from distance, while Fabricio Coloccini went close to glancing Drogba's cross into his own net.
Newcastle withdrew Hatem Ben Arfa for Gabriel Obertan and they had Santon to thank for preserving their lead when he cleared John Terry's 88th-minute header off the line.
Krul was booked for time-wasting but he need not have worried as Cisse sealed the win in the most outrageous fashion.