Jan Vertonghen and Gareth Bale gave the visitors a deserved half-time lead, but not for the first time at Old Trafford in recent years Tottenham were hit by a fierce second-half fightback.
However, Clint Dempsey scored in between efforts from Nani and Shinji Kagawa to keep Spurs in front, and after Wayne Rooney and Michael Carrick had struck the frame of Brad Friedel's goal, Tottenham clung on for the final whistle.
The result ended one of English football's longest winless streaks, as well as raising more questions over United's ability to regain the Premier League title as they slipped four points behind leaders Chelsea.
Tottenham have flattered to deceive in this fixture down the years, so much so that at no point did their two-goal cushion look secure.
They have even held a two-goal lead at half-time, as they did tonight, and got swept away by a second-half deluge. On that occasion, in 2009, United had Cristiano Ronaldo leading the thrilling comeback.
There was to be no such drama on this occasion, and United boss Sir Alex Ferguson may be left to reflect on a lack of physical presence in his midfield, which more than anything else was an area ruthlessly exposed by a rampant Tottenham.
There were only two minutes on the clock when Vertonghen strode between Nani and Carrick, drove into the United box and found the corner of Anders Lindegaard's net.
The Belgian's shot did take a significant deflection off Jonny Evans, but Vertonghen deserved his slice of good fortune for the adventure he had shown to take himself into a scoring position in the first place.
Rather than sting United into action, the early goal merely encouraged their visitors.
Bale revelled in the open spaces that opened up between Paul Scholes and Rio Ferdinand, with the former looking all of his 37 years at time during a below-par first-half display.
When Robin van Persie lost possession on the edge of the Tottenham area, Mousa Dembele thundered upfield with a purpose that left Scholes looking like he was treading water.
Bale took up the baton from his team-mate and duly sped past Ferdinand and into the box before beating Lindegaard rather too easily to make it 2-0.
Having resisted the temptation to name Rooney alongside Van Persie for the first time, Ferguson could delay the inevitable no longer and brought on the England man for Ryan Giggs at the break.
The move triggered a burst of three goals in four minutes, during which any semblance of a game plan for either side was completely ripped up.
Given the history of this fixture, it was no real wonder United should get two of them.
Rooney provided the assist for Nani's close-range effort, curling a low cross to the near post that invited the clinical finish.
Van Persie could claim the credit for United's second as he threaded a precise pass through the Tottenham defence that allowed Kagawa to beat Friedel.
Crucially, though, Tottenham struck their third goal in between United's brace, Bale once again exposing poor defending as he surged forward, and when Lindegaard was unable to hold the Welshman's low shot, Dempsey was on hand to slot home the rebound.
In Rooney, though, United retain that old slugger's instinct.
The striker thudded a brilliant free-kick against a post before Van Persie's dismal attempt to finish off a Carrick pass suggested again that it might not be United's day.
It was credit to Tottenham that they managed to clear their heads quickly enough to stand firm against the incessant wave of attacks that continued to come.
William Gallas clattered into a post such was his determination to keep Nani's far-post cross away from Rooney, then Friedel turned away a Scholes thunderbolt.
Carrick's header almost sneaked in but dropped against angle of post and bar instead.
United continued to surge forward, but the equaliser would not come.
And the sight of Evans hobbling off was an unhappy post-script given the defensive problems Ferguson has already encountered.