BACKGROUND Sinomenine (SIN) is an extract of the Chinese medicinal herb Sinomenium acutum; it has various pharmacological properties, including immunosuppression and anti-inflammation. The present study aimed to investigate whether SIN has an anti-depressant-like effect in a mouse model of depression induced by chronic unpredictable mild stress (CUMS), and to explore the underlying molecular mechanisms. MATERIAL AND METHODS A mouse model of depression was established and treated with different concentrations of SIN (30, 100, or 300 mg/kg). Then, behavioral tests, including sucrose preference test (SPT), forced swimming test (FST), and the tail suspension test (TST), were performed. The levels of norepinephrine (NE), 5-hydroxytryptamine (5-HT), and proinflammatory cytokines (interleukin-1β [IL-1β] interleukin-6 [IL-6], and tumor necrosis factor-α [TNF-α]) in the hippocampus of mice were detected by ELISA assay. The levels of p-p38, p-p65, NLRP3, ASC, and caspase-1 were measured by Western blot or/and qRT-PCR. RESULTS The results showed that SIN significantly relieved CUMSinduced depressive-like behaviors. Compared with the model mice, SIN treatment significantly increased the sucrose preference of the mice, and the immobility time in the forced swimming and the tail suspension test were shortened. In addition, SIN decreased CUMS-induced reduction in the concentrations of NE and 5-HT in the hippocampus of mice. SIN reduced CUMS-induced increases in the levels of IL-1β, IL-6, and TNF-α in the hippocampus of mice. Furthermore, activation of the p38MAPK-NF-κB pathway and the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome induced by CUMS were inhibited by SIN treatment. CONCLUSIONS In conclusion, our results indicate the antidepressantlike effects of SIN on chronic unpredictable mild stress-induced depression in a mouse model.