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.
Chelsea dominated the first half but failed to find a way through, with Willian and Cesc Fabregas both wasting good chances.
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 if they beat Everton later on Saturday.
Newcastle were able to celebrate a shock victory in which goalkeeper Jak Alnwick made some vital saves after coming on to make his debut at half-time following an injury to Rob Elliot.
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 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, who limped off and was replaced by 21-year-old 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 on the Newcastle goal.
Valiant defending from Coloccini and Taylor denied Costa on the turn, and Hazard saw a low shot hit the crossbar.
Newcastle then punished the leaders on the counter attack as Colback found Moussa Sissoko, he was unable to finish but the ball rolled to Cisse and the striker made no mistake.
Taylor was then dismissed a second bookable offence for a foul on Schurrle soon led to Drogba heading home a Fabregas free-kick after 83 minutes, setting up a tense finale.
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.
