The aim of this study was to investigate the role of 17 beta-estradiol (E2)-mediated oestrogen receptor (ER) in modulating the depressive-like behaviours of ovariectomy (OVX) mice and the associated mechanisms. E2 was administrated in OVX mice. The behaviour and physiological changes of OVX mice including immobility time in tail suspension test (TST) and forced swimming test (FST), levels of serum E2, inflammatory mediators, oxidative stress factors, indoleamine2,3-dioxygenase 1 (IDO1) and the neurotransmitters mediated by IDO1 activation were then recorded. Cell injury models established by lipopolysaccharide (LPS) or H2O2 stimulation in HT22 and BV2 cells were employed to further explore the mechanisms of E2's function. E2 treatment improved OVX-induced increase of immobility time in FST and TST. Meanwhile, E2 ameliorated the changes of inflammatory factors (NF-kappa B, TNF-alpha and IL-6), IDO1, IDO1-mediated TRP/KYN pathway and oxidative stress factors (iNOS, MDA, GSH and SOD) in the hippocampus of OVX mice. Interestingly, ER beta inhibitor abolished E2's inhibitory effects on the inflammation and IDO1-mediated TRP/KYN pathway; ER beta inhibitor also abolished E2's anti-oxidative stress effect. In cell experiments, ER beta small interfering RNA (siRNA) pretreatment reversed E2's anti-inflammatory effect on LPS-treated HT22 and BV2 cells and E2's inhibitory effect on IDO1 expression in LPS-treated BV2 cells. ER beta siRNA pretreatment also reversed E2's anti-oxidation effect on H2O2-treated HT22 cells. E2 exert the antidepressant function in OVX mice via ER beta-modulated suppression of NF-kappa B-mediated inflammatory pathway, oxidative stress factors and IDO1-mediated TRP/KYN pathway in the hippocampus.