Manchester City released a statement confirming De Bruyne had suffered a knee injury but said the extent of the issue is not yet known.
The statement said: “Kevin De Bruyne is undergoing tests on his right knee after sustaining an injury at training on Wednesday.
“The extent of the problem is not yet known and we will bring you further updates on Kevin’s condition in due course.”
According to Belgian football expert Kristof Terreur, De Bruyne could be out for as long as two months.
He tweeted: “Kevin De Bruyne (27) has suffered a knee injury in training.
“Full extent not known as yet, but fears that he might be out for a while (as in +2 months).”
De Bruyne made a late return to pre-season after reaching the World Cup semi-finals with Belgium.
But he came off the bench on Sunday in City’s 2-0 win over Arsenal.
De Bruyne is expected to be sent to see renowned specialist Dr Ramon Cugat in Barcelona to discover if he needs an operation.
But City boss Pep Guardiola will fear the worst because the injury has happened to the same knee De Bruyne badly damaged back in 2016.
De Bruyne missed 10 weeks of the season after damaging knee and ankle ligaments in an EFL Cup semi-final win over Everton at the Etihad.
If the news on De Bruyne is confirmed he could miss games against Huddersfield, Wolves, Newcastle, Fulham, Cardiff and Brighton.
He would also miss the start of the Champions League and Carabao Cup.
But Guardiola will hope De Bruyne is fit to face Liverpool on October 7.
Speaking earlier this month, former City defender Joleon Lescott claimed De Bruyne would be the only player who will not be rotated by Guardiola.
He said: “Everyone in City’s squad knows that there will be rotation. Probably apart from De Bruyne, every player will be expected to be involved in that rotation to get some rest.
“Mahrez is a top quality player, he’s recognised Premier League quality. Outside of City’s top players, he had the most assists in the Premier League.
“He’s coming in with title-winning experience, which a lot of the City players now have. It’ll be exciting for everyone to watch and see.
“In terms of him playing straight away, he may have to due to the lads being on international duty.
“Throughout the season, especially the forward players, will play a relevant number of games and have a great impact.”