Objective To investigate the effect of chronic corticosterone administration on learning and memory and expression of synapse-related proteins in mice. Methods C57BL/6J mice were randomly divided into control and corticosterone (CORT) groups (10 mice per group). CORT was dissolved in the vehicle (0.45% hydroxypropy-β-cyclodextrin, β-CD). Corticosterone (5 mg/kg/day) was orally administered in drinking water for 35 days. The control mice received vehicle (β-CD) in drinking water during the entire experiment. Social discrimination test and Morris water test were applied to evaluate the learning and memory impairment of the model mice. Results Both the mice of control and CORT groups were more interested in social (stranger cage) than the non-social (empty cage) experience. The control group increased the time spent with an unfamiliar mouse (stranger 2 cage). The mice of CORT group were not able to discriminate between an unfamiliar (stranger 2) and the familiar mouse (stranger 1). In the Morris water maze test, in contrast to the first 3 days, an increase in latency to reach the hidden platform (P < 0.05) was observed on day 4 in the CORT group compared with the mice of control group. CORT-treated mice showed a statistically significant decrease in the frequency in the platform, frequency in the target quadrant and distance in the target quadrant (P < 0.05, P < 0.05, P < 0.05) compared with the control group. The western blot analysis showed a notably decreased expression of PSD95, Syn-1 and p-erk in hippocampus in the mice of CORT group compared with the control group. Conclusions Chronic administration of corticosterone induces learning and memory impairment and decreases the expression of synapse-related proteins.