The 27-year-old was a key figure in City's historic Premier League winning campaign last term having contributed eight goals and 16 assists; missing just one league game all season.
"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.
The midfielder has not started either of City's matches so far this season, having returned late from the World Cup after helping Belgium secure third place in Russian Federation.
And The Times report that De Bruyne himself had a worrying reaction after he picked up the injury in training.
Due to being given three weeks off following the World Cup he did not play a role in the Community Shield win against Chelsea but came on for a cameo role of half an hour in the 2-0 opening Premier League victory over Arsenal last Sunday.
Now City will be without their Belgian star for a long period, but the emergence of Bernardo Silva and Phil Foden, along with the ever-present David Silva, will mean there is plenty of cover during his absence. It is worth noting, however, that he will likely miss at least two of City's Champions League group matches.