De Bruyne was making his first domestic start after returning last month from a right knee injury but went off after opposing defender Timothy Fosu-Mensah landed heavily on the player's left knee.
"(De Bruyne) underwent scans on Friday," City said in a statement on the club website https://www.mancity.com.
"No surgery is needed but he is expected to be out for between 5-6 weeks."
De Bruyne, who played a pivotal role in City's record-breaking title triumph last term, injured his right knee in City's opening league game in August.
The 27-year-old will now miss the Manchester derby against local rivals United on Nov. 11 as well as the rest of the Champions League group stages.
Pep Guardiola's side, currently top of the table with 26 points from 10 matches, host Southampton on Sunday.
The Spaniard told reporters he doubted the injury could have been avoided.
"Football is football, it was dynamic game with a lot of contact and this sometimes happens," said the manager.
"Kevin was out for two and a half (months), and we are sad for him. When you come back you cannot expect on day one he will be the player like we know he is. He needs time to settle, to take the rhythm, the pace, for everything.
"Yesterday he came back and did many things but it is what it is. Unfortunately he is injured, but fortunately it's not surgery and in between four and six weeks the doctor said he will come back."
(Reporting by Hardik Vyas in Bengaluru/Alan Baldwin; Editing by Toby Davis and Martyn Herman)
