De Bruyne delivered an imperious display including two goals on his first league start since November 6 after the Belgian star recovered from a bout of COVID-19.
Phil Foden, Jack Grealish, Riyad Mahrez, John Stones and Nathan Ake were also on target as Pep Guardiola's side ran riot at the Etihad Stadium.
City's seventh successive league victory put pressure on second placed Liverpool and third placed Chelsea, who face Newcastle and Everton respectively on Thursday.
The champions' biggest win this season equalled Liverpool's 1982 top-flight record of 33 victories in a calendar year.
"We're proud of the way we're playing. When you get these results, it is because individually they are brilliant," Guardiola said.
"Kevin, in these type of games when it is open up and down, is devastating as he can do what he wants. He's so important for us."
It was the joint biggest league defeat in Leeds' history, and shell-shocked boss Marcelo Bielsa said: "We've never had a performance like this. There is no justification. I have to take responsibility."
City took the lead in the eighth minute when Foden's shot was deflected in via Stuart Dallas's miscued attempt to clear off the line.
It was City's 500th Premier League goal in 207 matches under Guardiola, setting a new record that surpassed the previous fastest mark by Jurgen Klopp's Liverpool.
Grealish had managed just two goals for City since his British record £100 million ($132 million) transfer from Aston Villa.
In the 13th minute, the 26-year-old headed in Mahrez's cross to score for the first time since September.
De Bruyne marked his return with his first goal since October, converting Rodri's defence-splitting pass in the 32nd minute.
Mahrez added City's fourth in the 49th minute when his strike deflected in off Junior Firpo.
De Bruyne made it five in the 62nd minute with a thunderous 20-yard drive into the roof of the net.
Stones blasted home in the 74th minute, and Ake headed City's seventh four minutes later.
- 'Tough few days' -
Whether City's determined title defence survives without a brush with COVID-19 remains to be seen, as the new Omicron strain wrecks havoc.
The Premier League announced on Monday there had been 42 positive COVID-19 cases among top-flight players and staff last week -- the most recorded in any seven-day period since testing began during the 2019-20 season.
Manchester United's match at Brentford on Tuesday and Tottenham's trip to Brighton last Sunday were both postponed due to virus outbreaks.
United and Tottenham had several unnamed players test positive, while Brighton, Leicester, Norwich and Aston Villa were also hit by the virus over the last week.
Now all top-flight players and staff will have to take a lateral flow test every time they enter their club's training ground as part of the protocols.
Twice-weekly PCR testing will also be introduced after a meeting of the 20 clubs on Tuesday.
The increased testing sits alongside the other recently introduced emergency measures, including face coverings, limiting time in the treatment room and observing social distancing.
Norwich manager Dean Smith revealed his club had asked the Premier League for guidance over his bottom of the table team's Covid issues prior to Tuesday's 2-0 defeat against Aston Villa.
"It's been a tough few days. We've had a few Covid-related drop outs," Smith said before kick-off at Carrow Road.
Villa were also hit by Covid but they kept their focus to make it four wins from six games under new boss Steven Gerrard.
Smith had hoped for revenge on Villa just 38 days after his sacking.
But Jacob Ramsey ran from the halfway line to fire home in the 35th minute, and Ollie Watkins tapped in after 87 minutes.
"It's been a challenging week," Gerrard said. "We have to make sure we're very diligent with the guidelines. Nobody wants to see the situation deteriorate."