The Barcelona playmaker, whom a Spanish soccer federation (RFEF) spokeswoman said was suffering from an Achilles problem and had asked to be rested, joins fellow midfielder Cesc Fabregas and defender Raul Albiol on the injury list.
Fabregas damaged a hamstring during Arsenal's 1-1 draw with Sunderland on September 18 and was expected to be out for two to three weeks.
"We have two fundamental matches which are extremely dangerous," Del Bosque, who will lead Spain against Lithuania in his native Salamanca on October 8 and against Scotland in Glasgow on October 12, said at a news conference.
"Lithuania are a well-organised side who don't allow you space, with competitive players," he added.
"Scotland, playing at home, will be tough. We cannot afford the slightest stumble. We are preparing ourselves for a difficult test."
Spain, winners at Euro 2008, began their title defence with a 4-0 win in Liechtenstein earlier this month.
Squad
Goalkeepers: Iker Casillas (Real Madrid), Victor Valdes (Barcelona), Pepe Reina (Liverpool).
Defenders: Alvaro Arbeloa (Real Madrid), Sergio Ramos (Real Madrid), Carles Puyol (Barcelona), Gerard Pique (Barcelona), Carlos Marchena (Villarreal), Joan Capdevila (Villarreal), Nacho Monreal (Osasuna).
Midfielders: Xabi Alonso (Real Madrid), Sergio Busquets (Barcelona), Santi Cazorla (Villarreal), Andres Iniesta (Barcelona).
Forwards: Pedro (Barcelona), Jesus Navas (Sevilla), David Villa (Barcelona), David Silva (Manchester City), Fernando Llorente (Athletic Bilbao), Fernando Torres (Liverpool).
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