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.
However, the possibility of swapping the game would leave City facing six of their last eight matches away, including trips to Manchester United and Spurs.
Asked if City might reverse the fixtures, and switch October's game to the Etihad Stadium, Guardiola said: "I don't know - I can only say, if that happened, then four of our final five matches of the season would be away".
Manchester City boss Pep Guardiola says Kevin De Bruyne's knee injury can be put down to the extended workload of playing in the World Cup followed by coming straight back into a Premier League season.
De Bruyne was given three weeks off after the World Cup, having played over 500 minutes of action in helping Belgium reach the semi-finals at Russian Federation 2018.
After wildly successful spells at Barcelona and Bayern Munich, his first season in England with Manchester City didn't go to plan, with the Cityzens finishing third in the Premier League table.
That would see him miss crucial fixtures against Liverpool, Tottenham and Manchester United, as well as the first two rounds of fixtures in the Champions League.
Guardiola: "Football is not flowers, a good holiday and say everything is easy".
"We'll never know but my opinion is that we demanded a lot of the players". United finished above them last season.
More compelling insight is sure to come from the documentary series as it covers the title win but also crushing defeats to United and Liverpool. "We try to care for them as best as possible but you never know".
"No surgery is required, and the midfielder is expected to be out for around three months".
David Silva, who this week announced his global retirement, missed the Arsenal match and the Community Shield victory over Chelsea with a knee injury and could be back to face Huddersfield at the Etihad Stadium.
'He had a problem with his leg for the Arsenal game but he has trained good in the last two or three days'.