Depressive disorders are common psychopathologies highly comorbid with other mental diseases, especially post-traumatic stress disorder, with overt gender differences in susceptibility. The Disc1-Q31L mutant mice are characterized by depression-like behavior and disrupted molecular pathways involved in fear memory. Here, we assess the sex- and strain differences in learning and extinction of a conditioned passive avoidance response (CPAR) in male and female Disc1-Q31L mice vs. control C57BL/6 mice. Overall, male and female mice of both strains learned equally well but differed in fear memory extinction, i.e. the ability to form a new safety memory trace in the dark compartment of the test apparatus, previously associated with aversion. C57BL/6 female mice revealed poorer CPAR extinction than males, while both sexes showed strain differences in the extinction dynamics. While Disc1-Q31L male mice reached total extinction later than C57BL/6 males, Disc1-Q31L females exhibited no extinction throughout all 24 testing days. Collectively, this not only supports the role of Disc1 in fear memory extinction but also shows sex-dependent impact of its Q31L mutation in this process.