The Spaniard featured for his country on international duty but picked up an ankle knock in training, potentially opening the door for summer-signing Kevin De Bruyne to make his debut for the club.
Silva's absence will come as a massive blow to Pellegrini's side given the 29-year-old's excellent start to the new campaign, in which he was shortlisted for August's Premier League Player of the Month.
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And his injury comes at a particularly bad time given the Citizens' next opponents - Alan Pardew's rampant Palace.
The Eagles have enjoyed a tremendous start to the new season, taking nine points from a possible 12, and have made Selhurst somewhat of a feared fortress over the past few seasons.
However, City have similarly started the season with a bang, winning each of their first four games and keeping clean sheets in each, and pose as the greatest challenge Palace are likely to face this season.
There is good news for Sky Blues fans, though, with right-back Bacary Sagna seemingly fit to face the Eagles despite being substituted against Serbia in mid-week.
Wilfried Bony also returns having missed the past few games with an ankle injury.