Silva scored a late winner as City came from behind to beat West Ham 2-1 on Monday (AEDT), but suffered an injury in the act of finding the net.
He will not feature as City aim to finish the UEFA Champions League group stage with a 100 per cent record by beating Shakhtar Donetsk on Thursday, but of greater concern is his participation in the derby.
City already holds a commanding eight-point lead over their neighbours in the Premier League title race, and victory at Old Trafford on Monday could, even at this early stage, prove to be a decisive blow to United's hopes.
But Guardiola will be without the services of Silva due to an unspecified "problem".
Speaking at a pre-match media conference, Guardiola said: "Kevin De Bruyne is suspended and David Silva has a little problem. I don't know whether he will recover for Sunday.
"[Silva] felt uncomfortable after his goal. He felt something. Hopefully he can play on Sunday."
City has dropped points just once in the Premier League this season, but Guardiola is under no illusions of invincibility as it prepares to make the short trip to Old Trafford.
Guardiola said: "We just play to win the game. I assure you, sooner or later we will lose, but the next day we will recover. I can promise you we are going to try to win the game."
The Shakhtar match will mark Guardiola's 100th in the Champions League as a manager, having led Barcelona to glory twice in a celebrated spell with the Blaugrana.
"It's a nice number; it's a lot of games in a marvellous competition. Hopefully I can enjoy this for even longer," Guardiola said of his milestone.
"We are playing well but it does not mean we will go on to win the competition. The most important thing is that last month we were okay. We believe in what we can do."