Wayne Rooney and Cristiano Ronaldo scored twice as United closed the gap on Arsenal at the top with an emphatic victory at St James' Park.
Buoyed by news of the Gunners' 2-2 draw at Birmingham earlier in the day, the Reds dominated from start to finish to record their second convincing win over Newcastle in as many months.
Ronaldo set up Rooney for the opener before bagging his 28th and 29th goals of the season to put United out of sight.
Abdoulaye Faye pulled one back but Rooney's superb second and a late strike from substitute Louis Saha left Newcastle still searching for their first win since Kevin Keegan returned to the club.
Reds boss Sir Alex Ferguson, mindful of the need to keep his squad fresh as they chase three trophies, made four changes to his starting line-up after the midweek draw in Lyon.
In came Nani, Darren Fletcher, Michael Carrick and Carlos Tevez for Anderson, Paul Scholes, Owen Hargreaves and Ryan Giggs, with the latter two not even named on the bench.
The game got off to a typically up-tempo start, Steven Taylor denying Rooney with a last-ditch tackle before clearing Nani's scuffed shot off the goalline.
Keegan's men had conceded 11 goals in four games coming into the match and United threatened to open them up at will early on.
Carrick made a marauding run through the middle and played in Rooney on the right of the box, but the striker failed to pick out one of his team-mates with his pulled-back cross.
In the 24th minute, Rio Ferdinand had to be at his best to clear the ball in the box with Michael Owen poised to pull the trigger â€“ and a minute later United were ahead.
Ronaldo motored down the left, cut back inside Habib Beye and delivered a pinpoint cross to an unmarked Rooney, who volleyed home smartly at the back post.
Charles N'Zogbia was booked for bringing down Nani and Faye followed him minutes later after preventing Edwin van der Sar from making a quick clearance.
Milner looked the player most likely to get Newcastle back in the game and the winger's wicked left-foot cross deflected behind off Wes Brown as Owen lurked.
Owen became the third Newcastle player into referee Chris Foy's notebook for raising his studs as he contested a ball with Nemanja Vidic.
The Reds continued to pour forward in search of a second. Rooney and Ronaldo linked up well to create another opening, but the latter scuffed his shot wide from the left-hand side of the box.
Tevez missed a great chance to double United's lead five minutes before the break, heading a Nani
cross wide from seven yards.
But it wasn't long before the Reds had their second and it was Ronaldo who delivered the sucker-punch with his 28th goal of the season.
This time Carrick was the provider, the midfielder finding himself in acres of space as he drove forward and picking out Ronaldo, who calmly slotted past Shay Given.
Ferguson brought on John O'Shea for Patrice Evra at the break, while Keegan's only move was to replace goalkeeper Given with Steve Harper, suggesting he was more concerned with keeping the scoreline respectable than mounting a fightback.
The Magpies had the first chance of the second half when Damien Duff cut in from the left but saw his low shot saved by Van der Sar's legs.
But a couple of minutes later, Ronaldo ended the game as a contest with his second goal of the night. Fletcher intercepted Faye's poor clearance, put Ronaldo through on goal and the Portuguese star rounded Harper before finishing emphatically.
The 23-year-old was denied the chance to score his second Reds hat-trick when he was replaced by Saha in the 66th minute, to a standing ovation from the away support.
Nicky Butt was booked for a crude tackle from behind on Carrick before Vidic, still feeling the effects of Owen's late challenge in the first half, was replaced by Scholes.
Newcastle battled to offer a silenced St James' Park something to cheer, but by now United were in total command.
However, Faye ensured there was to be no repeat of the Tynesiders' 6-0 mauling at Old Trafford last month when he smashed home after a goalmouth scramble.
Scholes, looking for his first goal since August, almost netted United's fifth but, after a neat one-two with Nani, the midfielder's header was well pushed over by Harper.
Rooney's second goal and United's fourth was exquisite. With 10 minutes left, the striker collected the ball on the edge of the box after the Magpies had only half-cleared a corner and curled an unstoppable shot into the top-right corner.
Former United man Alan Smith came close to opening his account for the Magpies but saw his shot from the edge of the box tipped over by Van der Sar.
By now, Newcastle were all over the place at the back and Harper tipped over Saha's toe-poke inside the box.
But the Frenchman did get on the scoresheet in stoppage-time, firing home from inside the box to cap another resounding win for the Reds over their north-west rivals.