Christian Pulisic missed Borussia Dortmund's 2-1 defeat at Stuttgart on Friday after picking up a muscle injury.
Pulisic, who did not play in the United States' friendly against Portugal this week, stayed with Dortmund during the international break but was still a late scratch from the matchday squad.
A Dortmund statement said: "Christian Pulisic has been ruled out of Borussia Dortmund's match at VfB Stuttgart at late notice due to muscular problems."
Pulisic missed a DFB Pokal match last month with a minor knock but recovered in time to face Hannover, then started in the Champions League against Apoel before starring in a defeat to Bayern Munich on Nov. 4.
Dortmund were already without striker Pierre-Emerick Aubameyang, who was dropped for disciplinary reasons, while Alexander Isak was also sidelined by an injury
Maximilian Philipp started in their absence and scored Dortmund's only goal, bringing his season tally to six Bundesliga goals in 10 games.