To explore the effect of Chaihu Shugan Decoction on depressive-like behavior in rats and its underlying mechanisms.Methods:SPF-grade Sprague-Dawley(SD) male rats were selected for the experiment.A depressive rat model was established by a single intraperitoneal injection of lipopolysaccharide(LPS).Depressive-like behavior was assessed using the sucrose preference test and the open field test.After successful modeling，the rats in each group were treated with the corresponding interventions.Protein expression levels of multiple endocrine neoplasia type 1(Men1)，cysteinyl aspartate-specific protease 3(Caspase-3)，nuclear factor kappa B(NF-κB)，interleukin-1β(IL-1β)，and mRNA levels in the hippocampal tissue were measured using Western blot and real-time PCR，respectively.The mechanism by which Chaihu Shugan Decoction affected depressed rats was ultimately explored.Results:A single intraperitoneal injection of LPS induced depressive-like behavior in rats，including a dull expression，dull eyes，reduced appetite，and decreased activity.Chaihu Shugan Decoction significantly restored the body weight and motor ability of depressed rats(P<0.05，P<0.001).Compared to the blank group，the Menin expression level in the depression group was significantly reduced(P<0.001)，while Caspase-3，NF-κB，and IL-1β expression levels were significantly increased(P<0.001).Compared to the depression group，the low，medium，and high-dose groups of Chaihu Shugan Decoction significantly increased Menin expression levels(P<0.05，P<0.01，P<0.001)，significantly decreased NF-κB expression levels(P<0.05，P<0.001)，and significantly reduced Caspase-3 and IL-1β expression levels(P<0.001).Conclusion:Chaihu Shugan Decoction improves depressive-like behavior in rats by regulating the Menin/Caspase-3 signaling pathway，promoting Menin expression，and inhibiting Caspase-3 expression.