The Australia international sustained the injury to his left knee in training and will go under the knife later in January.
As well as ending his season, the injury looks likely to cost him a place at the World Cup in Brazil with the Socceroos.
Leverkusen said in a statement: "Robbie Kruse suffered a tear of the anterior cruciate ligament in his left knee in training and so is likely to be missing for Bayer 04 in the entire second half of this season.
"The Australia international picked up the injury on Friday at training and, on Saturday, an MRI scan showed the worst outcome."
Kruse moved to the BayArena from Fortuna Dusseldorf in the summer and has made 21 appearances for Leverkusen this season, scoring three goals.
Sami Hyypia's side currently sit second in the German top flight and will resume their Bundesliga campaign at Freiburg next Saturday,