Abstract: Background and Objective: Perimenopausal depression is caused by the impaired function of the ovarium prior to menopause and characterized by a persistent feeling of sadness and loss of interest. Electroacupuncture (EA) therapy has been demonstrated to be effective in patients with depression. The effects of EA in perimenopausal depression as well as the underlying mechanisms remain unclear. This study aimed to elucidate the therapeutic effect of EA on perimenopausal depression and its correlation with the CREB/BNDF signaling pathway to understand the mechanisms underlying the EA effect. Materials and Methods: Chronic Unpredictable Mild Stress (CUMS) combined with bilateral ovariectomy (OVX) were used to establish a rat model of perimenopausal depression. The Open Field Test (OFT) and sucrose preference tests were used to examine the anxiety level and anhedonia effect of OVX+CUMS rat model and the effects of EA. The MTT assay and flow cytometry were used to detect the cell viability and apoptosis of hippocampal neurons. The immunohistochemistry and ELISA assay were utilized for measuring the proteins expressions and RT-PCR for mRNA expressions, respectively. Comparisons among more than two groups were made using one-way analysis of variance (ANOVA) followed by the Least Significant Difference (LSD) test. Results: The EA at the "Shenshu", "Baihui" and "Sanyinjiao" points could reverse the increased and reduced sucrose preference induced by CUMS and OVX. Meanwhile, the reduced cell viability, increased cell apoptosis and impaired function of hippocampal neurons in the perimenopausal depression model rats were prevented by EA treatment. Moreover, EA increased p-CREB and BDNF expression in the hippocampal neurons and this effect was found to be suppressed by the CREB antagonist KG-501. Conclusion: The EA treatment could rescue the impairment induced by OVX+CUMS via CREB/BDNF pathway activation. Taken together, the results suggest that EA could be a potential therapy for perimenopausal depression.