De Bruyne withdrew from the Belgium squad in midweek and City boss Pep Guardiola said he was not able to put a timescale on the midfielder's return.
With a busy fixture schedule that sees City playing four Premier League and three Champions League matches in the next three weeks, any injury will be a significant setback.
"Unfortunately De Bruyne is out, but the rest of the players came back well," Guardiola told a news conference. "I don't think it is [serious], but the next games I think he will be out. We will see."
The City boss also refused to confirm whether Aguero would be in his squad for the visit of Arsenal and will be careful with the Argentine striker, who has missed nearly four months after injuring his knee in a 5-0 victory over Burnley in June.
The 32-year-old returned to training with the first team during the international break and has a chance of being part of Guardiola's squad.
"He’s trained well and we are happy, we need a striker," Guardiola added. "We played without them but he’s trained three or four days and we are happy to see him back on the pitch after a long time."
City have been without a recognised striker after Gabriel Jesus picked up an injury in the first game of the season against Wolves and the Brazilian is still yet to return to training.
"He had an injury in some muscles that mean we cannot take a risk," Guardiola said. "It is in the front part of his leg and if it’s injured we’d lose him for a long time. I don’t know on the time.”
Guardiola started the season with a slew of injuries but he is starting to get more players fit and available. Midfielder Ilkay Gundogan is available after recovering from Covid-19 while Joao Cancelo and Bernardo Silva featured in Portugal's three matches during the international break.
The Catalan was happy that his players were able to get minutes on the pitch after a difficult and shortened pre-season for many of his squad.
"I never complain about international games, I know how important for the players for their countries, it’s a privilieged and they have to do it," he said. "UEFA and FIFA have their own tournaments. We want the players to come back fit but they can get injured here training with us.
"Bernardo, Joao and other players could not have a normal pre-season so it was good for them to get the rhythm."
Raheem Sterling could also be available to face the Gunners despite pulling out of the England squad with a hamstring injury.