The Barcelona midfielder was left out of the trip to Villarreal on Sunday and has withdrawn from the national squad ahead of the games with France and Macedonia.
The Barcelona midfielder missed Sunday's La Liga match at Villarreal, with club coach Luis Enrique confirming that the 30-year-old was experiencing "some knee discomfort."
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And the experienced playmaker has now been ruled out of Thursday's friendly in Paris and the visit of Macedonia for a Euro 2016 qualifier next Monday, with Barcelona confirming on its official website that the player has withdrawn from the camp.
Vicente del Bosque has not called up a replacement, so he will pick from a 22-man squad for the two games.
Iniesta earned his 100th cap in the 3-0 victory over Australia in Spain's final World Cup group match in Brazil. He is eighth in the list of all-time appearances for Spain.