Abstract: The study is aimed to investigate the anti-depressant effect of puerarin in rat model of depression induced by chronic unpredictable mild stress (CUMS) and to explore the relevant mechanism. We established the depression rat model using CUMS. Rats were randomly divided into control, CUMS model, CUMS +fluoxetine (10 mg·kg^-1) and CUMS +puerarin (50, 100, 200 mg·kg^-1) groups. Drugs or vehicle were administrated after stress induction for 21 days. Open-field test (OFT), sucrose preference tests (SPT) and forced swim test (FST) were used to evaluate the anti-depressant effects of puerarin. The reactive oxygen species (ROS), prostaglandin E₂ (PGE₂) level, superoxide dismutase (SOD) and catalase (CAT) activities in hippocampus were determined by ELISA. Expression of IL-1β, TNF-α, and IL-10 was measured by qRT-PCR and Western blot analysis. Behavioral test suggests that crossing score, rearing score in OFT and sucrose preference index in SPT of model group were significantly lower than the control group (P< 0.01), while immobility time in FST was significantly increased (P< 0.01). Compared with those in control group, the ROS and PGE₂ level increased significantly (P< 0.01), SOD and CAT activities were decreased significantly (P< 0.01), the mRNA and protein level of IL-1β, TNF-α, and IL-10 were increased significantly (P< 0.05 or P< 0.01) in rats of CUMS. Puerarin and fluoxetine ameliorated those changes induced by CUMS. Puerarin improved the depression-like behaviors of rats induced by CUMS, and the mechanism may involve in the antioxidant and anti-inflammatory effects.