The Bayern Munich number one featured in Friday's comfortable Euro 2016 qualifying victory over Gibraltar in Nuremberg, but will play no part against Vicente del Bosque's side as a precautionary measure.
Germany coach Joachim Low will turn to either Borussia Dortmund's Roman Weidenfeller or Hannover keeper Ron-Robert Zieler for the clash between the current and previous world champions in Vigo.
Low told the German Football Association's official website: "I would have liked to play with the best team possible against Spain but we didn't want to take any risks with Manuel.
"We have two excellent alternatives in the form of Roman Weidenfeller and Ron-Robert Zieler, who will have more than deserved an appearance against Spain. I know that I can completely rely on them both."
Spain will head into the game on the back of a Euro 2016 qualifier against Belarus on Saturday.
