De Bruyne, who came on as a substitute in City's 2-0 victory over Arsenal in their first league match of the season last weekend, suffered the injury in training this week.
"Manchester City can confirm Kevin De Bruyne has suffered a lateral collateral ligament lesion in his right knee," the club said in a statement.
"No surgery is required and the midfielder is expected to be out for around three months."
Guardiola speculated that the extensive demands on players and the lack of a break over a demanding World Cup summer may have been a contributory factor to De Bruyne's injury.
De Bruyne, City's player of the season in 2017-18, scored eight goals and provided 16 assists as City won the league title with a record-breaking 100 points.
The 27-year-old Belgium international then helped his country progress to the World Cup semi-finals with an outstanding tournament in Russia.
De Bruyne, who missed 12 games in 2016 after injuring the same knee during a League Cup semi-final win over Everton, will not be available for City's group matches in the Champions League, nor key league fixtures against Liverpool, Tottenham Hotspur and the Manchester derby against United on Oct. 7.
'PART OF THE GAME'
Speaking before City's league match against Huddersfield Town on Sunday, Guardiola said: "We are going to try to do our best, whether he is coming back at the start of December or end of November to be there (at the top of the table).
"My advice to him now would be to rest and take the holidays he didn't get after the World Cup...
"Of course, these injuries are never wanted but you accept it, it's part of the game and especially part of the amount of games and seasons (players have).
"They don't rest. It was a tough season last season and they come back with a short recovery and we're demanding from the first moment 'come on, let's go.' And, of course, human beings have a limit."
De Bruyne was involved as Belgium secured a third-place finish in Russia by beating England 2-0 on July 14, one month before the start of the new Premier League campaign.
Asked if he thought the minimal break after the World Cup was responsible for the injury, Guardiola added: "I don't know exactly but in my opinion when we demand a lot of the players, I'm sure it can have an influence.
"When you are fresh in your legs after normal vacations, that doesn't happen."
(Reporting by Shrivathsa Sridhar in Bengaluru and Ian Chadband; Editing by Christian Radnedge)
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