The inspirational De Bruyne faces up to 10 weeks on the sidelines after suffering knee and ankle ligament damage in Wednesday’s Capital One Cup semi-final victory over Everton.
The 24-year-old had made a big impact after coming off the bench in that game, scoring and setting up another goal for Sergio Aguero.
This is typical of the impression he has made since signing from Wolfsburg last summer, having now scored 12 goals and assisted 12 others.
Pellegrini said: “It’s a challenge for the squad and of course it’s a challenge for the players that play where Kevin does.
“I think that Raheem (Sterling), Jesus (Navas), David (Silva) will have more responsibility knowing that Kevin is not here.
“It’s impossible to have 25 Kevin De Bruynes in the squad, but I answer the same as when we couldn’t play with Sergio Aguero.
“You have some players that are impossible to replace because they are top players — but we did it. We replaced Kun, we replaced David and we replaced Vincent Kompany. That is why we are involved in all the competitions and three points from the leaders of the Premier League.
“Now we have to replace Kevin.”
Pellegrini hopes De Bruyne can be back in action by the end of March and expects the player to deal with his setback positively.
He said: “He’s not happy with what has happened but he will be optimistic, and it’s very important to have his clear mind that he can return before if he works hard. I’m sure that he will make all his efforts to do it.”
City’s victory over Everton kept them alive in four competitions but Pellegrini claims winning the quadruple remains unlikely.
His immediate concern is today’s Emirates FA Cup fourth-round trip to Aston Villa.
He said: “It’s not a target that we have in mind at the moment because it is not a realistic target.
“We have to play against Aston Villa tomorrow. If we fail tomorrow, we finish talking about that.”