This study aims to explore the antidepressant mechanism of icariin.Mice (SPF,KM) were randomly divided into five groups,including the control group,model group,fluoxetine hydrochloride group,high-dose icariin group,and low-dose icariin group.Mice were subjected to different stressors for 56 days except control group mice.Meanwhile,groups of mice were intragastrically administered fluoxetine hydrochloride (10 mg/kg),high-dose icariin (50 mg/kg),low-dose icariin (25 mg/kg) or a vehicle once per day for 56 consecutive days.On the 53 th-56 th day after administration,behavioral tests were performed.At the end of the treatment,blood was collected using cardiac puncture under anesthesia.ELISA was used to detect interleukin-6 (IL-6),IL-10,5-hydroxytryptamine (5-HT),dopamine (DA),and norepinephrine (NE) level.The expression of IL-6,IL-10,inducible nitric oxide synthase(iNOS) and cluster of differentiation 206(CD206) mRNA in brain tissue were detected using quantitative real-time PCR (RT-PCR).Western blot was used to detect the expression of iNOS and CD206 protein in brain tissue.BV-2 cells were cultured in vitro,and CCK-8 method was used to detect the cytotoxicity of icariin.After the exposure of BV-2 cells to lipopolysaccharide（LPS） (100 μg/mL) and icariin (15,25 μg/mL) for 24 h.The expression of iNOS and CD206 mRNA in brain tissue were detected using immunofluorescence.We found that the model of depression caused by chronic unpredictable mild stress was successful.Icariin reduced the level of IL-6 and the expression of IL-6,iNOS mRNA in the brain tissue of depression mice,increased the level of IL-10,5-HT,DA,NE and the expression of IL-10,CD206 mRNA,inhibited the brain iNOS protein and increase the expression of CD206 protein,and improved depression-like behavior in model mice.The results of in vitro studies show that icariin could reduce the expression of iNOS and protein in BV-2 cells stimulated by LPS,and increased the expression of CD206 and protein.The results show that icariin inhibits the M1 phenotype transformation of microglia and promotes the M2 phenotype transformation,thereby improving the depression-like behavior of model mice.