De Bruyne was City's player of the season last term, scoring 12 goals and providing 21 assists as his side won the Premier League and EFL Cup.
Bernardo Silva started and scored in the win against Arsenal and the Portugal worldwide could remain a starter in De Bruyne's absence.
"Kevin is a great player and it's just unfortunate that it's happened to him in training but there's more than enough depth in the squad", said the England global of his teammate.
"Kevin De Bruyne is undergoing tests on his right knee after sustaining an injury at training on Wednesday", read a club statement on its website.
"We don't just rely on one player".
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Man City may have a catalogue of star players in their ranks but De Bruyne's absence will unquestionably be a huge loss - especially given the timing - and it now appears that punters have taken note.
The Amazon Prime series "All Or Nothing" is an eight episode behind-the-scenes series of City's romp to the Premier League crown. "Obviously it's a big loss but we've got more than enough cover".
"He is very important".
The 27-year-old came on for the final 30 minutes in City's 2-0 win against Arsenal on the opening weekend last Sunday and cut short his holiday in a bid to play against the Gunners.
"I am privileged to be manager of Manchester City".