Objective: To investigate the effect of curculigoside on mice with simulated perimenopausal depression. Method: Gavage with high, medium, small dose of curculigoside once daily for 30 d consecutive days. Record the related behavior index. The wet weights and viscera indexes of the mouse uterus, thymus, and spleen were measured. Half of the brain was homogenized and tested for 5-HT and DA concentrations. The levels of serum E2, T, FSH, and LH were measured as well. Finally, histological changes in the uterus, thymus, spleen, and hypothalamus were observed under a light microscope. Result: curculigoside can enhance the activity and latency time of the mice, increase mouse memory, and decrease electric shocks and immobility times in the TST and FST experiments. Mice treated with curculigoside showed significantly enhancement in viscera indexes of the thymus, spleen, and uterus; significantly elevated levels of serum E2 and T; significantly increased brain 5-HT and DA concentrations; significantly decreased levels of serum FSH and LH; and improvements in the histopathological lesions of the uterus, hypothalamus, thymus, and spleen. The high dose of curculigoside produced the best results. Conclusion: All doses of curculigoside are associated with reversing hormone (E2, T, FSH, and LH) disorders in perimenopausal syndrome and adjusting imbalanced 5-HT and DA levels, representing a therapeutic effect in perimenopausal depression.