The Real Madrid midfielder tore a cruciate ligament during Germany’s 1-1 friendly draw against Italy in Milan on Friday and now misses the side’s friendly international against England at Wembley on Tuesday.
The 26-year-old former Stuttgart player will, will now have surgery.
“This is a bitter setback for Sami,” said Germany coach Joachim Low. “But he always thinks positively and that is why I am optimistic he will be ready and fit when the World Cup starts.”
Khedira, who has featured 44 times for Germany, suffered the injury in a second-half tackle on Italy midfielder Andrea Pirlo.
Germany are one of the favourites for next summer’s World Cup in Brazil after qualifying with nine wins from their 10 matches.