De Bruyne signed a six-year contract with Manchester City on August 30, 2015, reportedly for a club record fee of £55 million (€75 million).

On September 12 against Crystal Palace, he made his team's Premier League debut, coming on in the 25th minute to take Sergio Agüero's place due to injury.

De Bruyne scored four goals in 24 minutes in City's 5–1 triumph at Wolverhampton on 11 May 2022, the third-fastest hat-trick in Premier League history.

Andy Hinchcliffe of Sky Sports called it "23 minutes of footballing genius" and Jeremy Wilson of The Daily Telegraph called it "one of the finest displays in Premier League history."

De Bruyne is the fourth player to win the accolade more than time. He won Player of the Year for the fourth time with Manchester City.

De Bruyne's half-volley in a 2–2 draw against Newcastle was selected Premier League Goal of the Month for November.

De Bruyne scored his 50th City goal in all competitions in their 2–1 comeback win over Real Madrid on 26 February 2020.

After scoring 13 goals, contributing 20 assists, and generating 104 open-play opportunities, he was named Premier League Player of the Season.

He was also selected to the PFA Team of the Year and won PFA Player of the Year, becoming City's first winner.

He represented Belgium at the 2018 FIFA World Cup, when they beat England in the third-place match. He was named to the FIFA World Cup Dream Team.