The decrease of estrogen is a common cause of menopausal depression, but there is still a lack of effective drugs with no side effects. Previous studies have shown that resveratrol, as a natural extract of polyphenols, has antidepressant effects in a variety of depression models, but the effect and mechanism of resveratrol on menopausal depression are unclear. In this study, B6.Cg-TgN (Thy-YFP-H)-2Jrs transgenic mice were ovariectomized combined with chronic restraint stress (OVX-CRS) to establish a model of menopausal depression. The antidepressant effect of resveratrol was evaluated by tail suspension test (TST), forced swimming test (FST), sucrose preference test (SPT) and novel inhibition feeding test (NSFT). Using the characteristic expression of yellow fluorescent protein (YFP) in excitatory neurons of transgenic mice, the effects of resveratrol on the density of dendrites and dendritic spines were evaluated by three-dimensional imaging technique. BDNF, cofilin1 and p-cofilin1 were quantitatively analyzed by qPCR or/and immunofluorescence quantification to explore the effects of resveratrol on synaptic plasticity in hippocampus and medial prefrontal cortex (mPFC) and its mechanism. The results revealed that CRS significantly increased the immobility time in TST, prolonged the feeding latency and reduced the food intake in NSFT, and decreased the sucrose consumption in SPT. Simultaneously, treatment with resveratrol significantly improved depression-like behaviors. In addition, resveratrol significantly increased the density of dendrites and dendritic spines in hippocampus and mPFC, augmented the density of filopodia-type spines and thin-type spines in hippocampal CA1, and upregulated the density of thin-type spines in mPFC. Consistent with these changes, resveratrol treatment significantly increased the density of p-cofilin1 immunoreactive dendritic spines and the mRNA level of BDNF in these brain regions. The results suggest that although there are some sex differences in the efficacy and antidepressant mechanism of resveratrol based on neuronal plasticity, resveratrol, the results of which are similar to those in the male model of depression, can improve the synaptic plasticity in the corresponding brain regions by upregulating BDNF levels, enhancing the phosphorylation of cofilin 1, increasing the density of dendrites and dendritic spines in the hippocampus and mPFC, and ultimately alleviating menopausal depression-like behaviors.