Aymeric Laporte will miss the Carabao Cup final on Sunday and Manchester City's forthcoming games against Manchester United and Real Madrid after being ruled out for a month with a hamstring injury.
The French defender, who was sidelined for almost five months earlier this season with knee ligament damage, sustained his latest injury during the first half of City's Champions League round-of-16 first-leg victory against Real in the Bernabeu on Wednesday.
Sources told ESPN Laporte was in a battle to be fit for a crucial stage of the season and City manager Pep Guardiola confirmed on Friday that the 25-year-old is facing another spell out of the team as a result of his latest setback.
"It's a hamstring injury," Guardiola said. "The prognosis is very long, three weeks or month, more or less.
"We tried to avoid it [by managing his performances since returning from knee injury], but it's happened and, after four or five months injured, it can happen.
"It's tough for him, I imagine, but players have to overcome it.
"Life is not easy. Always in the world, there are guys who overcome the bad moments who don't complain that the world is against them.
"You must just accept it, work harder and try to come back in the best condition possible."
Guardiola, meanwhile, delivered a more positive update on the fitness of winger Leroy Sane, who has been sidelined since suffering a cruciate ligament injury during the Community Shield clash against Liverpool in August.
The Germany international, who is a summer target for Bayern Munich, has travelled to London with City's Under-23 team to play against Arsenal on Friday at the Emirates.
"Leroy is with the Under-23s, it's part of the training," Guardiola said. "I don't want to put a target on him.
"We'll see the game, how does he feel to play against Arsenal, but it's good for him to be back."