Spurs completed an unbeaten home season and signed off from White Hart Lane with a historic and deserved win over the much-changed Reds.
The victory ensured Tottenham bow out from their home of 118 years with 17 wins from their 19 home fixtures (with only draws against Liverpool and Leicester denying them an extraordinary 100% record).
Mauricio Pochettino's side scored early in each half - through Victor Wanyama and Harry Kane - to seal the runners up spot as United went down in north London for the second successive week.
Wanyama's opener came from Spurs first attack as Ben Davies picked out the Kenyan to head in his third goal of the season from close range in the sixth minute.
Juan Mata and Wayne Rooney went close with headers and Anthony Martial flashed an effort narrowly wide having burst clear on the counter-attack.
At the other end, United were indebted to David de Gea who saved well from Son Heung - min and then palmed away Christian Eriksen's follow up.
Kane headed against the bar and de Gea produced another superb stop to keep out Dele Alli's dipping drive from distance.
Spurs threatened to run riot but the Spaniard came to his side's rescue again shortly before the break when he denied Kane with his foot.
The second period began in the same way as the first as Spurs moved 2-0 ahead with their first attack.
Eriksen's sublime free-kick from wide on the left was met by Kane, who stole in ahead of Chris Smalling to flick the ball home from six yards.
Kane flashed an effort inches wide moments later before Martial did the same for United after he had linked up well with Mata.
United continued to press and finally got a foothold in the game with 20 minutes to play.
Martial was the Reds most promising outlet going forward and made an impact again when his run and resultant cross picked out Rooney who couldn't miss from two yards to give United hope.
Phil Jones cleared off the line from Alli after an exchange of passes with Kane as Spurs to establish their two-goal advantage once more.
United substitute Marcus Rashford then had a chance to salvage a point, but blasted wide when clean through under pressure from a posse of Spurs defenders.
That proved to be the last action, as the emotional Spurs fans stormed the pitch at full-time to celebrate the end of the White Hart Lane era.
Overall team performance: 6/10
United Faithful Man of the Match: David de Gea