The France midfielder marked his home debut with a 68th-minute strike to level the game at 2-2 and then blasted home a brilliant winner to further boost Alan Pardew's survival mission.
Chelsea looked to be on their way to a first victory in four attempts in all competitions when, after Frank Lampard had cancelled out Jonas Gutierrez's first-half opener, Juan Mata curled home a superb 61st-minute effort. But a rejuvenated Newcastle refused to accept defeat and Sissoko snatched a dramatic win.
It was meant to be striker Demba Ba's day as he returned to St James' Park, but he departed prematurely with a bloodied nose to catcalls after just 42 minutes. The Magpies followed him down the tunnel just a few minutes later with the advantage at the end of a thoroughly entertaining 45 minutes of football.
The confidence gained by Newcastle in Tuesday night's 2-1 victory at Aston Villa with new boys Mathieu Debuchy, Sissoko and Yoan Gouffran in the team was in evidence as the home side set about their task with some relish.
The opening goal arrived four minutes before the break and from an unusual source. Newcastle's final ball had at times been ordinary, but Davide Santon produced a telling cross to allow Gutierrez to glance a deft header across Petr Cech and into the bottom corner to send the home fans into raptures.
Chelsea returned after the break in determined mood to pin the Magpies back into their own half, and as Pardew's men retreated, Papiss Cisse found himself isolated in attack despite the best efforts of Sissoko and Gouffran.
They were back on terms within 10 minutes in stunning style when Lampard controlled Cole's pass on his chest, took another touch and then lashed a dipping shot past the helpless Tim Krul.
Things might have been worse for Newcastle on the hour when James Perch gifted the ball to Oscar and the visitors broke at pace for Mata to cross for Lampard, but he headed straight at Krul. The Dutchman was not so fortunate seconds later, however, when Fernando Torres laid the ball back to Mata, who curled a superb left-foot shot over Krul and into the top corner.
However, the home side dragged themselves back into it with 22 minutes remaining when, after Cech had parried Gouffran's effort, Sissoko steered the rebound home. Then, in the final minutes, Cech could not deny the Frenchman when he exchanged passes with Santon before drilling a sweet drive past him to win the match for Newcastle.