The Argentinian, who has a calf injury, has scored 19 goals this season - 18 of them in his past 16 appearances - and is certain to be missed by Pellegrini's men.
The challenge for Pellegrini is now to shuffle his resources to try to maintain the potency of his free-scoring side. Here, Press Association Sport looks at some of his options.
The Spaniard has settled in quickly at City and formed a formidable partnership with Aguero. His own contribution to the goals tally has been impressive, with 13 goals to his name. He is physically strong and makes a good foil for the more nimble Aguero. Remains to be seen how he might operate with a different partner.
The Bosnian offers something different to Aguero but he is still a well-rounded player; strong in the air and good with his feet. He may not be as clinical or consistent as Aguero but he is still a good finisher. The form of Aguero and Negredo has pushed him to the bench but he is trusted by Pellegrini.
In contrast to Negredo, little has gone right for £22million man Jovetic since he arrived in the summer. The former Fiorentina striker has rarely been fit and managed just five appearances. His luck was summed up this week as he finally looked set for a chance in the Capital One Cup at Leicester after overcoming a calf injury, only to be struck down by illness. Will hope his chance comes soon.
Pellegrini appears to be a fan of playing two strikers but he must decide whether to persist with that or try something different in Aguero's absence. Dzeko actually operated as the lone frontman at Leicester. If continuing with this approach, one option might be to push playmaker Silva forward to operate just behind the main striker.
Much has been said about John Guidetti's potential but illness and injury have hampered the Sweden Under-21 international's progress and he still appears some way off a first-team spot. Marcos Lopes, 17, is another highly-rated prospect but the club are not likely to rush him through.