Yet despite De Bruyne's considerable absence, Guardiola insisted he could see a "Silva lining".
This could be Bernardo Silva's moment - after his scintillating start to the season - to make the grade from City's favourite luxury item on the bench to the main man.
And with David Silva potentially ready to rejoin the fray for Sunday's visit of Huddersfield Town, Guardiola believes the 32-year-old Spaniard also still has a key role to play now that he has hung up his international boots.
Naturally, De Bruyne, who scored eight goals, set up 16 more and created the lion's share of chances in City's landmark 100-point season, is going to be missed.
After all, no player in Europe's top five leagues provided more assists.
City remain spoiled for choice in midfield, as Liverpool manager Jurgen Klopp noted on Saturday when he told Sky Sports how sorry he was about De Bruyne's misfortune.
"They still have options of course, like they always do," Klopp said. "They have brought in Riyad Mahrez, but they can all play in different positions. Nobody needs to worry about Man City and their quality, there's still a lot there."
Guardiola's ability to bring the best out of intelligent players even when moving them into new, unaccustomed positions makes his City side perhaps the most flexible the Premier League has seen.
Yet even amid the bewildering array of midfield talent that Guardiola still has at his disposal, with the likes of Ilkay Gundogan, Fabian Delph and Mahrez on board, Bernardo Silva had already staked his claim to taking the reins.
He was superb in the Community Shield win over Chelsea and opening league victory at Arsenal, with his performance in the Wembley curtain-raiser hailed as a "masterpiece" by Guardiola.
He also noted that currently it was "Bernardo and 10 players more" - such was his level of play.
"He is so intelligent, he is clever, he is a fighter, a competitor," Guardiola gushed.
Last season, Silva played 35 league matches, but started only 15, a figure that should rise considerably this season, particularly in light of De Bruyne's injury.
But Guardiola believes David Silva too could be rejuvenated now that he has decided to end his distinguished FIFA World Cup-winning international career.
"Big congratulations to him," said Guardiola, reporting that Silva had overcome a slight knock that kept him out of the Arsenal match and was back in contention for Sunday's game.
"More than 100 games, winning the World Cup, two European Championships as one of the most fascinating, incredible players in the history of Spain.
"Nobody pushed him, he decided to finish his international career so he could rest a little bit more with his wife, family and his little boy while continuing to play with us."
