The 27-year-old playmaker has sustained a minor thigh problem while away with his national side and has therefore returned to his club Manchester City for treatment.
Silva was an unused substitute in Spain's 2-0 FIFA World Cup qualifier in Finland last Friday, a game that saw club team-mate Alvaro Negredo come off the bench and score.
This represents a second withdrawal in as many days for Spain coach Vicente del Bosque, after Real Madrid midfielder Isco left the squad due to an ankle injury on Sunday.
City will hope former Valencia star Silva is ready for their Premier League meeting with Stoke City on Saturday.
City manager Manuel Pellegrini already has a number of injury problems, with captain Vincent Kompany and new signing Martin Demichelis both out of action with hamstring and knee issues respectively.
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