The Senegalese striker was the difference with two impressive goals, and Pepe Reina's dismissal for a headbutt on James Perch made it a terrible day for Kenny Dalglish's men
The Senegalese striker scored a fine header and then rounded the keeper to add a second before Reina's head-butt on Perch saw the visitors reduced to 10 men.
Captain Fabricio Coloccini was missing for the home side but Cheikh Tiote returned after missing the victory against West Brom.
Jonjo Shelvey came into to the Liverpool starting XI for the first time since January’s FA Cup victory over Oldham whilst Jose Enrique, Craig Bellamy and Andy Carroll all made returns to their former club.
The first chance of the game fell to Jonjo Shelvey whose dipping shot took a wicked deflection and flew just over the bar.
A Steven Gerrard free-kick then landed on the head of Martin Skrtel but he failed to find the target with a header from inside the six-yard box.
Then there was controversy as Andy Carroll broke through on goal and went down ahead of a challenge by Newcastle goalkeeper Tim Krul.
Replays showed that the Liverpool number nine had gone down far too easily, though, and referee Martin Atkinson booked him for diving, much to the joy of the Toon faithful.
Liverpool continued to have the better of proceedings and, after a lovely ball out wide by Luis Suarez, Craig Bellamy’s cross was deflected onto the bar by Krul.
From the resulting corner Danny Simpson appeared to handle on the line after Mike Williamson’s header was diverted goal-bound, but nothing was given despite the Merseysiders' protests.
Against the run of play it was the home side who took the lead in the 19th minute. A lovely run from Hatem Ben Arfa led to him supplying a wonderful cross to the back post for Cisse, who guided a well angled header into the far corner with help from the woodwork.
Despite going behind the away side continued to press, and were nearly level after a ball in from Bellamy fell for Carroll, whose header just cleared the bar.
The Magpies were offering a threat on the break and nearly doubled their lead when a Demba Ba shot took a wicked deflection off Martin Skrtel, but it went just past the post.
Just before the break a Danny Guthrie cross was met by the goalscorer Cisse, but this time his header didn’t find the target.
A couple of minutes after the half time interval the Geordies were extremely close to extending their lead. A floated cross in from the right by Yohan Cabaye was beautifully guided goalwards by Williamson, whose header agonisingly came back out off the post.
But just before the hour mark Newcastle got their two-goal cushion.
A swift passing move ended with Ba pushing a ball across the area and, after both Ben Arfa and Jamie Carragher failed to latch on the loose ball, Cisse calmly rounded Pepe Reina and found the back of the net. The Sengalese international appeared to be in an offside position but the goal stood.
Liverpool came straight back on the offensive and, after Krul couldn’t deal with a cross into the box, it appeared Suarez would halve the deficit. However, a remarkable block from James Perch further frustrated the visitors.
Things then went from bad to worse just under ten minutes from time for Liverpool.
After Reina recovered a Williamson header Perch tripped the Spaniard up. The Reds keeper then appeared to headbutt the Newcastle man, who went down, and the referee produced a red card. Reina will now miss the reds next three games, including the FA Cup semi-final with Everton.
Faced with a dispirited 10-men, Newcastle then coasted to a victory which saw them move 11 points clear of their beaten rivals.