Objective To study the mechanism of antidepressant effect of Baihe Zhimu decoction based on NLRP1 inflammasome. Methods A chronic unpredictable mild stress（CUMS）induced depression mouse model was constructed. C57BL/6J mice were randomly divided into a control group, CUMS group, low-dose Baihe Zhimu decoction group, high-dose Baihe Zhimu decoction group, and MDP group（NLRP1 activator）. After continuous administration for 4 weeks, the behavioral characteristic of mice was investigated. The levels of mice hippocampal inflammatory factors IL-1β、IL-6,TNF-α, and neurotransmitters 5-HT, NE, and DA were detected by ELISA. The expression of inflammasome related proteins NLRP1, ASC, and caspase-1, as well as related proteins in BDNF/TrkB and ERK/AKT/mTOR signaling pathway were detected by Western blot. Immunofluorescence was used to detect changes in BDNF expression in the hippocampus of mice. Results Baihe Zhimu decoction inhibited the activation of NLRP1 inflammasomes in the hippocampus of CUMS mice, improved their behavioral characteristics, increased the level of neurotransmitters in the hippocampus, and reduced the inflammatory response. The NLRP1 activator MDP reversed the above effects of Baihe Zhimu decoction. Baihe Zhimu decoction increased BDNF, TrkB expression, and phosphorylation levels of ERK, AKT, and mTOR proteins, which could be reversed by MDP. Conclusion Baihe Zhimu decoction improved depression like behavior in CUMS mice by inhibiting NLRP1 inflammasome activation and hippocampal neuroinflammatory response, and thereby activating BDNF/TrkB and ERK/AKT/mTOR signaling pathway.