Although neuroprotective effects of estrogen on postmenopausal women have been recognized, an associated increased incidence of uterine and breast tumors has jeopardized the clinical use of estrogen. This study was designed to evaluate the neuroprotective effects of a novel phytoestrogen α-zearalanol (α-ZAL), on ovariectomized (OVX) rats. Adult Wistar rats were ovariectomized or sham-operated and treatment with equivalent doses of 17β-estradiol or α-ZAL for 5 wk. Uteruses have been weighted and stained by hematoxylin and eosin for morphology analysis. The expression of synaptophysin and parvalbumin in hippocampus were evaluated by immunohistochemistry assays. Our experiments indicated that the synaptophysin and paravalbuminpositive areas were significantly decreased in the OVX group compared to the sham group, α-ZAL or 17β-estradiol administration can reverse the effects. Although α-ZAL and 17β-estradiol treatments reconciled uterus weight loss which was induced by ovariectomy, the effect of α-ZAL was less than 17β-estradiol. This result suggests that α-ZAL may effectively abate neurons loss in the hippocampus while slightly promoting weight gain of the uterus.