The Belgian maestro scored City's second goal, after Ilkay Gundogan had opened the scoring, and Raheem Sterling added two more in a thumping win that provisionally sent Pep Guardiola's men 14 points clear at the summit.
Victory embellished the record for consecutive English league wins City had set in Wednesday's 4-0 win at Swansea City and the breathtaking manner of it was further evidence of their apparent invincibility.
Guardiola, who also saw substitute Gabriel Jesus miss a penalty, has equalled the run of 16 straight league wins he engineered with the great Barcelona team that won a La Liga and Champions League double in 2011.
Spurs were left to lick their wounds after a fifth defeat of the campaign -- one more than in the entirety of last season -- which sent them slithering down the table to seventh.
It could have been even worse for Mauricio Pochettino's men, who replied through Christian Eriksen, had referee Craig Pawson not shown only yellow cards to Harry Kane and Dele Alli for two ugly second-half fouls.
The absence of David Silva due to what City described as "personal reasons" opened the door for Gundogan and the Germany midfielder seized the opportunity by scoring his first goal of the season in the 14th minute.
Pochettino had opted for a midfield diamond in a bid to deny City space in the middle of the pitch, but De Bruyne still found room to spring his team forwards with trademark piercing passes.
The visitors gave their opponents only one moment of discomfort in the first half, Kane shaping a shot fractionally wide from the edge of the box.
- Sweet revenge -
=================
Peripheral in the first half, Kane became a central figure early in the second as a fired-up Spurs tried to make a fist of it.
City almost had reason to rue Pawson's leniency when Kane took aim from 25 yards and Ederson had to leap to his right to touch the ball behind.
Eager to give Spurs something to think about at the other end, Guardiola sent on Jesus for Sergio Aguero, who tossed his gloves to the ground in disgust as he made his way off.
The City bench erupted in fury shortly after when Alli caught De Bruyne high on the ankle in an awful challenge and was shown only a yellow card.
But after receiving treatment, De Bruyne claimed sweet and immediate revenge, gathering Gundogan's pass and surging into the box before unleashing a left-foot shot that beat Lloris for pure power.
City could even afford to squander a penalty, Jesus driving the ball against the left-hand post and Sterling putting yet another shot over an open goal after Jan Vertonghen had caught De Bruyne.
Eriksen's stoppage-time strike, a low effort with his left foot, offered scant consolation.
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