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The defeat also led to Spurs sacking interim coach Cristian Stellini on Monday, with Ryan Mason taking over head coach duties until they find a replacement.
A game billed as a crucial six-pointer in the race to secure Champions League qualification was effectively all over before the clock had reached 10 minutes as fifth-placed Tottenham collapsed like a pack of cards.
Callum Wilson scored in the 2-0 win for the home side.
Casemiro scored in United's 2-0 win at the Wembley on Sunday.
The 31-year-old had been missing since the February 6 earthquake.
Manchester United cemented their top-four place, moving level on points with Newcastle as goals by Casemiro, Luke Shaw and Marcus Rashford sealed a 3-0 victory at Old Trafford.
The Gunners maintained their 100 per cent home record. They have 40 points from 15 games.
City are second in the table with seven points, two behind leaders Arsenal. Newcastle are sixth with five points.
Thanks to their superior goal difference, Spurs will only need a point at already-relegated bottom side Norwich City on Sunday to qualify for Europe's elite competition.
The result stretched Manchester United interim manager Ralf Rangnick's unbeaten start to four games in all competitions.
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