Objective: To investigate the antidepressant-like effects of Xiaoyao pill in corticosterone-induced depression-like behaviors and to explore its molecular mechanism. Methods: Fifty SPF male mice were randomly divided into 5 groups: control group, corticosterone group, fluoxetine group (20 mg/kg), low dose Xiaoyao pill (200 mg/kg) group, high dose Xiaoyao pill group (600 mg/kg). Depression-like symptoms were induced by subcutaneous injection of corticosterone. After administration with Xiaoyao pill for 35 days, the depressive-like behaviors were evaluated by sucrose preference test and forced swimming test. The levels of corticosterone in serum and the concentrations of brain-derived neurotrophic factor (BDNF) in hippocampus of mice were measured by ELISA. Results: The results of sucrose preference test showed that corticosterone decreased the sucrose preference, while Xiaoyao pill increased the sucrose preference. Forced swimming test showed that corticosterone reduced the immobility time of mice, while Xiaoyao pill reversed the increase. The results of ELISA showed that long-term corticosterone injection increased the levels of serum corticosterone and decreased the concentrations of BDNF in hippocampus. On the contrary, Xiaoyao pill decreased the corticosterone levels and increased the BDNF concentrations. Conclusion: Xiaoyao pill could reduce the serum corticosterone levels and increase the hippocampal BDNF levels, in turn improve the neurotrophic system, which leads to the antidepressant-like effects.