Abstract: To study the effects of S-equol（Eq） on chronic restraint stress（CRS）-induced depressive-like behavioral in mice and the underlying mechanisms. Mice were randomly divided into control group（Con）, CRS model group（CRS）, Eq-Low group(Eq-L, 10 mg·kg^-1), Eq-Medium group(Eq-M, 20 mg·kg^-1) and Eq-High group(Eq-M, 40 mg·kg^-1). After pre-administration with Eq for 2 weeks, the CRS group and Eq groups was conducted by continue restraint in 10 hours daily for 28 days. The effects of CRS and Eq on the mice were investigated by body weight（BW）, open field test（OFT）, sucrose preference test（SPT）, and tail suspension test（TST）. In addition, corticosterone（CORT） levels in serum as well as interleukin-6（IL-6）, interleukin-1β（IL-1β）, tumor necrosis factor α（TNF-α）, norepinephrine（NE）, dopamine（DA）, superoxide dismutase（SOD）, malondialdehyde（MDA）, and catalase（CAT） levels in cortex of mice were evaluated to explore the molecular mechanism of antidepressant effect. The results of behavioral tests showed that CRS and Eq administration were found to have no influence on the locomotor activity of mice（P＞0.05）compared to those of control group. However, the body weight and sucrose preference index of the CRS-treated mice was significantly lower than that of control mice（P＜0.001）. At the same time, CRS treatment remarkably increased the immobility time of mice in TST（P＜0.01）. Meanwhile, administration with Eq(10, 20 and 40 mg·kg^-1) significantly elevated the sucrose consumption percent and decreased the immobility time when compared with the CRS-treated group（P＜0.05）. In addition, CRS treatment significantly increased the levels of CORT in serum（P＜0.001）, decreased the contents of TNF-α, IL-6, IL-1β and MDA（P＜0.05）, and elevated the levels of NE, DA, SOD, and CAT（P＜0.05） compared to those of control mice. Eq administration significantly reversed these changes of CRS-treated mice. These findings demonstrated that Eq treatment significantly alleviated the depressive-like behavior induced by chronic restraint stress, possessing the antidepressant-like effects. The mechanisms underlying the antidepressant-like effects of Eq may be related to normalize the hypothalamic-pituitary-adrenal axis（HPA）, mediate neuroinflammation, elevate the monoamine neurotransmitter levels, and alleviate the oxidative stress.