The Senegal striker headed the first from a Hatem Ben Arfa cross before sidestepping Reina and side-footing home for a clinical second.
It was a miserable afternoon for an out-of-sorts Liverpool, who felt they should have been awarded a first-half penalty when Danny Simpson appeared to handle on the line, while Cisse looked offside in the build-up to Newcastle's second.
Liverpool had Reina sent off with seven minutes remaining when he was judged by referee Martin Atkinson to have headbutted Newcastle's James Perch after being tripped up by the defender.
Replays showed that Perch made the most of whatever contact there was when the two players came together in an angry confrontation.
Newcastle remain sixth, two points behind fourth-placed Tottenham Hotspur who host Swansea City later on Sunday, while Liverpool are eighth, a point behind local rivals Everton.
Liverpool striker Andy Carroll was making his return to his former club and was given an indication of the tough afternoon he was facing when he was roundly booed stepping off the bus.
The 35-million pounds ($55.92 million) striker, who has scored only five Premier League goals since his move last January, did not help his cause with the home fans when he was booked for diving after 10 minutes following a theatrical fall in the area.
Cisse, who wears the number nine shirt vacated by Carroll, gave Newcastle the lead when he met Ben Arfa's far post cross and headed it cleverly back across goal and into the net off the post.
His second was controversial, with the Senegalese seemingly in an offside position when the ball was played into the area by Demba Ba.
The assistant's flag stayed down, however, and Cisse was perfectly placed to finish neatly when the ball arrived at his feet following a touch from Ben Arfa.
Reina's late sending off was a sign of frustration, according to manager Kenny Dalglish whose team have now won only two Premier League games in 2012.
"The boys have shown frustration and that's probably why Pepe Reina was sent off," he told the BBC.
"It was the frustration of being behind. When Andy Carroll comes off and runs up the tunnel it's purely disappointment and frustration. It's all very well having that but we have to manage that and channel it in a proper way.
"If we don't stick together and have trust in each other it is going to be a lot more difficult."
