The France international - skippering the side in place of injured Fabricio Coloccini - played a clever one-two with Sammy Ameobi before steering a 78th-minute strike home as Newcastle recorded a fifth straight Premier League victory for the first time since April 2012.
QPR had seemed on their way to a first away point of the season, as Harry Redknapp's side stood firm for much of the game under plenty of Newcastle pressure.
As Alan Pardew saw his side toil against a resolute backline, he also watched on as Ryan Taylor - who made his first top-flight start in 32 months - limp off with what seemed like another knee problem in the first half.
However, Sissoko was the man to lift spirits around St James' Park on what would have been a frustrating day, scoring his first Premier League goal of the season.
Another three points for Newcastle move them up to fourth, while QPR slip back to the foot of the table thanks to Burnley's surprise 2-1 win at Stoke City.
Rob Green’s sloppy clearance almost deflected off Jack Colback and in for Newcastle after six minutes during a keenly contested opening period.
And Pardew, who brought in Taylor and Mike Williamson for injured pair Mehdi Abeid and Coloccini, saw his side continue to threaten with Remy Cabella having Newcastle's first shot on target.
The Frenchman's tame effort was easily saved, though, before Charlie Austin muscled Paul Dummett off the ball and fired wide on a rare foray forward from QPR.
Taylor tested Green with two long-range strikes while Massadio Haidara's effort was blocked well by Richard Dunne before Taylor’s involvement was cruelly cut short.
The former Wigan Athletic man limped off visibly upset having appearing to hurt his right knee, dampening the hosts' mood after what had been a largely positive half for the hosts.
Matters were almost made worse for Pardew when Dunne's looping header needed tipping over by Tim Krul shortly before the interval.
Newcastle began the second half in positive fashion, continuing to deliver dangerous crosses, although QPR were able to deal with the aerial threat well.
Joey Barton - making his return to St James' Park for the first time since leaving Newcastle in 2011- almost found Austin with a lofted ball before Redknapp saw close-season signing Sandro collide with team-mate Yun Suk-young.
The Brazilian also made his return to action recently following a long-term knee injury but, like Taylor, was forced off.
However, it was skipper Sissoko who ensured yet another win for Pardew's side when he rounded off a slick exchange to register his first league goal since March.
