Xavi has an Achilles problem and asked coach Vicente del Bosque to rest him for the Lithuania match on Friday in Salamanca and the trip to play Scotland in Glasgow on Tuesday.
His role in directing Spain's play around the centre of the pitch and threading passes through to the forwards will likely be taken on by his Barcelona team mate Andres Iniesta.
"Xavi is important in this team but there are others who can do his job calmly and confidently," Marchena told a news conference on Wednesday at Spain's training base outside Madrid.
"We hope to be prepared so that we don't notice anyone's absence," he added.
Injuries have also deprived Spain of fellow midfielder Cesc Fabregas and forwards Fernando Torres, Pedro and Jesus Navas.
Marchena said the team had moved on from last month's humbling 4-1 defeat by Argentina in a friendly in Buenos Aires and were confident of securing a second successive win in Group I on Friday.
"We know that that's football and it can happen that one day you lose," he said. "We analyse the mistakes internally so that they are not repeated. That's football and you can lose sometimes. It doesn't matter."
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