The Belgian striker, who was starved of service despite making several good runs, had a great chance to break the deadlock at the start of the second half but his first-time effort was beaten away by Ederson.
But City continued to dominate the second period with Raheem Sterling firing a shot narrowly wide.
Thomas Tuchel brought on Timo Werner and Callum Hudson Odoi but almost instantly City took the lead when captain De Bruyne went past N'Golo Kante and curled a wonderful shot into the bottom corner from outside the box.
And City held on to make it 12 wins in the league in a row, giving Pep an early birthday present for Tuesday, while Chelsea remain second.
Mason Mount's omission surprising.
Chelsea defended brilliantly for large parts but were second best in midfield throughout with thir final ball lacking. Pulisic was picked ahead of Mount and did little to provide service for Lukaku. Mount's pace and creativity could have swung the game more in the Blues' favour but he remained on the bench until the 81st minute with Werner and Hudson-Odoi brought on earlier, both of whom have been less reliable than the England midfielder this season. Mount, who has seven goals in the Premier League this season, looked more livelier than Pulisic and Ziyech when he eventually came on but had little time to impact the game.
MANCHESTER, ENGLAND - JANUARY 15: Jack Grealish of Manchester City and Mason Mount of Chelsea after the the Premier League match between Manchester City and Chelsea at Etihad Stadium on January 15, 2022 in Manchester, England. (Photo by Simon Stacpoole/Of
Image credit: Getty Images
MAN OF THE MATCH
Raheem Sterling (Man City): The England midfielder was a threat throughout with his pace and jinking runs and was unfortunate not to end up on the scoresheet. He also created good chances for Phil Foden and Jack Grealish.
MANCHESTER, ENGLAND - JANUARY 15: Raheem Sterling of Manchester City shoots past Malang Sarr of Chelsea during the Premier League match between Manchester City and Chelsea at Etihad Stadium on January 15, 2022 in Manchester, England. (Photo by Matt McNult
CHELSEA: Kepa 7, Thiago 7, Rudiger 7, Sarr 7, Azpilicueta 7, Kante 5, Kovacic 6, Alonso 6, Pulisic 4, Ziyech 5, Lukaku 6. Subs: Werner n/a, Hudson-Odoi n/a, Mount n/a.
39' - GOOD SAVE! Kovacic gives it away, it falls to Grealish who bursts into the box and his stabbed shot is saved by Kepa for a corner which is cleared. Grealish should have scored.
47' - LUKAKU CHANCE! Lukaku is through on goal, his shot is beaten away by Ederson off his line. Ziyech makes a mess of the rebound. Seconds earlier, Sterling had a penalty shout but the ref said play on.
70' - WHAT A GOAL! De Bruyne with a fantastic run and curling shot into the bottom corner from outside the box.
Kevin De Bruyne has now scored five goals against Chelsea in the Premier League, the most by a former player against the Blues.