Objectives: Jiao-tai-wan (JTW) has been often used to treat insomnia and diabetes mellitus. Recent studies found its antidepressant activity, but the related mechanism is not clear. This study is to evaluate the therapeutic effects of JTW on chronic restraint stress (CRS)-induced depression mice and explore the potential mechanisms.Methods: CRS was used to set up a depression model. Mice in different groups were treated with 0.9 % saline, JTW and fluoxetine. After the last day of CRS, the behavioral tests were conducted. The levels of neurotransmitters, inflammatory cytokines and HPA axis index were detected and the protein expressions of NLRP3 inflammasome complex were determined. H&E, NISSL, TUNEL and immunofluorescence staining were used to observe histopathological changes and the activation of microglia and astrocytes. The potential mechanisms were explored via network pharmacology and verified by Western blot.Results: The assessment of liver and kidney function showed that JTW was non-toxic. Behavioral tests proved that JTW can effectively ameliorate depression-like symptoms in CRS mice, which may be related to the inhibition of NLRP3 inflammasome activation. JTW can also improve the inflammatory state and HPA axis hyperactivity in mice, and has a protective effect on CRS-induced hippocampal neurons damage. The network pharmacology analysis and the results of Western blot suggested that the antidepressant effects of JTW may be related to the MAPK signaling pathway.Conclusion: Our findings indicated that JTW may exert antidepressant effects in CRS-induced mice by inhibiting NLRP3 inflammasome activation and improving inflammatory state, and MAPK signaling pathway may also be involved.