Schalke said in a statement the 30-year-old had suffered a partial tear of a ligament in his right knee after colliding with Wolfsburg goalkeeper Diego Benaglio.
"The team doctors think he is looking at a break of several weeks," Schalke said.
Huntelaar, the Bundesliga's top scorer two seasons ago with 29 goals, scored twice in Schalke's opening match, a 3-3 draw with Hamburg SV, a week ago.
Schalke finished fourth last term and host Greek side PAOK Salonica on Wednesday in the first leg of their Champions League playoff tie.
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