Yohan Cabaye grabbed the crucial goal just after the hour mark as the Magpies claimed their first win at Old Trafford since 1972 to move four points clear of the ninth-placed Red Devils.
It was another subdued performance from David Moyes' men after their 1-0 loss to Everton on Wednesday, as Robin van Persie had a goal disallowed for offside and Patrice Evra hit the post.
Tim Krul also made a couple of decent saves but Newcastle were good value for their victory, which leaves Man United 12 points off top spot, having played a game more than Arsenal, and increases the pressure on Moyes.
Seven changes from the midweek defeat by Everton, including the return of Van Persie following a four-match absence with a groin strain, should have had a positive impact.
But the additional mobility compared to Wednesday was lost amid the tentativeness of a team who looked scared to lose in front of a crowd on the brink of a very negative reaction.
Too often invention was spurned in favour of safety, which in turn reinforced the defences of a solid Newcastle outfit, who never looked in danger of coughing up the type of goals they did at Swansea on their last outing.
Player-of-the-month Krul pulled off a decent save from Phil Jones in the early stages but had little else to do in the first-half.
Fabricio Coloccini made an excellent clearing header to prevent Nemanja Vidic getting to Adnan Januzaj's cross, whilst the youngster was robbed in the box brilliantly by Yoan Gouffran.
Javier Hernandez also had a penalty appeals rightly waved away when he dived in the box, but United rarely threatened.
With Cheick Tiote controlling midfield and Loic Remy remaining on the move, United's defence did not look as settled as Newcastle's.
And when Evra was caught out of position, it allowed Remy to slide a brilliant pass through for Mathieu Debuchy, whose thunderous first-time shot was turned away one-handed by David de Gea.
De Gea moments later repelled a close-range Debuchy header to at least ensure United reached the break level.
Moyes appeared to have used the interval wisely, judging by the sense of purpose his side had at the restart.
Krul saved from Hernandez and Januzaj before Evra met a Nani corner with purpose and sent a header bulleting against the post.
Vurnon Anita had no chance to react as the rebound struck him on the hand from barely six inches. As the ball was flashing straight across goal and the diversion helped take it away to safety, United were adamant that they should have had a spot-kick. Instead referee Andre Marriner waved play on, just as he did when Tiote cut down Evra close to the Newcastle goal-line moments later.
Cabaye then fired Newcastle in front on the 61-minute mark. Evra's clearing header bounced back off Moussa Sissoko, allowing the Newcastle man a free run into the area, before cutting back a perfect cross to invite Cabaye's first-time finish, albeit via a slight deflection off Vidic.
Wilfried Zaha was introduced for his Premier League debut and Anderson also came on as Moyes tried to change the game, and United thought they had their equaliser when Van Persie headed in from a free-kick, but the flag was correctly raised for offside.
United continued to push forward but to little effect and when Marriner called time on another sorry day, there were boos from some of the home fans as Alan Pardew rushed on to congratulate his Newcastle players.