Major depressive disorder (MDD) is a worldwide life-threatening disorder with high incidence and high mortality. Besides, the neurotrophic effects of estrogen have been demonstrated in many neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's disease (PD). However, the mechanistic interplay between depression, neuroinflammation and estrogen remain unclear. Here, this study investigated the effect of E2 on neuroinflammation and depressive-like behaviors induced by ovariectomy (OVX), as well as the underlying mechanism. We found the anti-depressant effect of E2 through behavioral experiments and verified the anti-apoptotic effect of E2 on the depressive hippocampus in mice, and finally we showed that E2 alleviated inflammatory response and reversed depressive-like behaviors by inhibiting gp130/JAK1/STAT3 signaling pathway via combining with estrogen receptor-β (ER-β) in vivo and vitro. These results suggested that E2 possesses potent anti-depressive action, which might be mediated via inhibition of neuroinflammation and apoptosis impairment by promoting the interaction between gp130 and ER-β.