Background: Depression is a psychiatric disorder with depressed mood and even suicide attempts as the main clinical symptoms, and its pathogenesis has not yet been fully elucidated. Brain derived neurotrophic factor (BDNF) plays an important role in the pathogenesis of depression. Purpose: The main aim of the present study was to evaluate the effectiveness and reveal the potential mechanisms of bilobalide (BB) intervention in alleviating depression-like behaviors by using chronic unpredictable mild stress (CUMS) mice via mediating the BDNF pathway. Methods: Behavioral assessments were carried out by using the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). CUMS mice were randomly divided into 5 groups: CUMS + solvent, CUMS + BB low, CUMS + BB medium, CUMS + BB high and CUMS + fluoxetine. Total serum levels of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) were measured by ELISA. Expression of TNF-α, IL-6, AKT, GSK3β, β-catenin, Trk-B and BDNF in the mouse hippocampus was assessed by western blotting. Results: BB treatment reduced the levels of pro-inflammatory cytokines (IL-6 and TNF-α) and increased the protein expression of BDNF in the hippocampus region of the CUMS mice. Moreover, BB treatment enhanced the AKT/GSK3β/β-catenin signaling pathway which is downstream of the BDNF receptor Trk-B in the hippocampus of these mice. Conclusions: Overall, the experimental results indicated that BB reverses CUMS-induced depression-like behavior. BB exerts antidepressant-like effects by inhibiting neuroinflammation and enhancing the function of neurotrophic factors.