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.
The result ended one of English football's longest winless streaks, as United 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 lasy night, 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.
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. Rather than sting United into action, the early goal merely encouraged their visitors.
When Robin van Persie lost possession, Mousa Dembele thundered upfield with a purpose that left Paul Scholes looking like he was treading water.
Bale took up the baton from his teammate and sped past Rio Ferdinand before beating Lindegaard 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 striker on for Ryan Giggs at the break.
The move triggered a burst of three goals in four minutes.
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 his low shot, Dempsey netted the rebound.
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