INTRODUCTION: Depression is a prevalent and persistent mental disease characterized by symptoms such as anhedonia, anxiety, and desperation. Although our previous study shows that Xiaochaihutang (XCHT) upregulates hippocampal brain-derived neurotrophic factor (BDNF) levels in depressed mice and rats, the underlying mechanism requires further clarification. OBJECTIVES: To assess the mechanism by which XCHT regulates hippocampal BDNF expression in chronic social defeat stress (CSDS)-induced mice. METHODS: Adult C57BL/6J mice were exposed to CSDS for 10 consecutive days to establish a depression model. XCHT treatment (2.3, 7 and 21 g/kg, intragastric administration) was administered for 4 consecutive weeks. Behavioral assessments were sequentially conducted to investigate the antidepressant effects of CSDS-induced XCHT. Golgi staining, immunofluorescence, immunoblotting, real time fluorescence quantitative polymerase chain reaction and chromatin immunoprecipitation were then employed to study the mechanisms underlying the regulation of XCHT on hippocampal BDNF expression. RESULTS: XCHT significantly improved CSDS-induced anhedonia, social avoidance, recognition memory impairment, and anxiety/depression-like behaviors in mice. XCHT significantly promoted neuronal complexity and dendritic spine maturation in the mouse hippocampus. Furthermore, XCHT reversed the CSDS-induced reduction in the number of hippocampal BDNF CONCLUSION: XCHT may enhance the transcripts of specific Bdnf exons I, VI and VI by upregulating the H3K18 acetylation at the corresponding Bdnf promoters, which consequently promotes BDNF expression levels. This further promotes neuronal plasticity in the hippocampus, ultimately ameliorating anxiety/depression-like behavior in CSDS-induced mice.