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".
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.
Vicente del Bosque has not called up a replacement, so 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.