Atletico Madrid said Koke (30) picked up a thigh injury in Saturday's 1-0 win at Athletic Bilbao, leaving the Spain midfielder just weeks to recover before the World Cup in Qatar.
Koke had started physiotherapy and rehabilitation sessions, Atletico said on Monday without providing a timeline for his return, but reports in Spanish media said he would be out for three weeks.
Koke, who has 67 caps, was substituted in the 81st minute of Atletico's win.
Spain, who are in Group E at the World Cup with Germany, Costa Rica and Japan, have yet to announce their final squad for the tournament. They begin their group campaign on November 23rd against Costa Rica.