The Senegal striker came off the bench to hit a decisive double against Jose Mourinho's men, with the away side's loss marking their first league defeat of 2014-15
The Senegal international fired home four minutes after coming on in the second half before adding what proved to be a decisive second goal with 12 minutes to play, ensuring Jose Mourinho has still never masterminded a Premier League win at St James' Park.
|VIEW FROM ST JAMES' PARK
|By Graeme Bailey
Jose Mourinho must truly hate the North East - last season Sunderland ended his glorious home run, now Newcastle have ended this season's unbeaten record and any hope that his side could go down in history is invisible.
Mourinho has never won at St James' Park but for much of the game they looked the most likely.
Then Papiss Cisse came off the bench and helped himself to two goals. Didier Drogba pulled one back with Steven Taylor also sent-off for Newcastle, and although they had chances to level the home side held on for a famous win.
They were made to pay after 57 minutes, as Cisse netted his sixth league goal of the season by tapping home Sammy Ameobi's cross.
Cisse then doubled Newcastle's advantage, and although Didier Drogba pulled a goal back after Steven Taylor had been sent off for a second bookable offence, for the second time in the space of a week Chelsea dropped points in the North East.
Defeat enables Manchester City to close the gap to just three points at the top of the table if they beat Everton on Saturday.
Alan Pardew rang the changes after Newcastle's draw at Burnley on Tuesday, with Fabricio Coloccini and Remy Cabella two of five players coming in.
Chelsea welcomed back leading scorer Diego Costa from suspension at the expense of Drogba, while John Obi Mikel replaced the banned Nemanja Matic in midfield.
The visitors dominated possession in the first half and had their first sight of goal after 10 minutes, when Willian fired narrowly wide of Rob Elliot's goal after good work from Costa and Eden Hazard.
Chances continued to come for Chelsea but Willian was again guilty of missing a great opening 18 minutes with a curling effort 18 minutes in, before Cesc Fabregas saw a low shot deflected wide.
Having soaked up plenty of pressure, Newcastle eventually began to pose more of an attacking threat and Thibaut Courtois had be alert to deny Jack Colback in the 31st minute, the midfielder collecting an Ayoze Perez pass inside the penalty area only to be denied by the Belgium goalkeeper.
Newcastle's goalkeeping problems worsened at half-time as Elliot, in for the injured Tim Krul, limped off and was replaced by 21-year-old Jak Alnwick.
The debutant commanded his area well and, having weathered another spell of Chelsea pressure, Newcastle opened the scoring.
Sammy Ameobi made good ground down the left, Cahill failed to deal with his low cross and Cisse had the simple job of tapping home from close range.
Mourinho introduced Andre Schurrle and Drogba from the bench and Chelsea began to lay siege to the Newcastle goal.
Valiant defending from Coloccini and Taylor denied Costa on the turn, and Hazard saw a low shot hit the post.
Newcastle then punished the leaders on the counter attack as Colback found Moussa Sissoko, who then rolled the ball to Cisse and the striker made no mistake.
Taylor was then dismissed a second bookable offence for a foul on Schurrle, which led to Drogba heading home a Fabregas free-kick in the 83rd minute, setting up a tense finale.
But Alnwick came to Newcastle's rescue in the closing minutes with saves to deny Costa and Filipe Luis as Newcastle held on for all three points.