Howedes, who has only recently returned from a thigh injury, suffered a muscle tear to his left adductor in Tuesday's 3-1 UEFA Champions League defeat at Real Madrid, a result that saw them exit the competition.
Schalke say the 26-year-old is not available for selection "in the coming weeks".
Club coach Jens Keller told the club's official website: "This is very bitter," while sporting director Horst Heldt said the news was "brutal".
Howedes' injury reduces the options available to Keller, with fellow defenders Christian Fuchs (knee), Felipe Santana and Atsuto Uchida (both hamstring) and Jan Kirchhoff (ankle) also sidelined.
Jefferson Farfan, Marco Hoger and Dennis Aogo (all knee) and Christian Clemens (hip) are all battling injuries too.
The news is a blow for Schalke, who have risen to third in the Bundesliga table on the back of successive league wins over Hoffenheim and Augsburg.
They host rock-bottom Eintracht Braunschweig on Saturday.
