BACKGROUND:Post-partum depression is the most prevalent form of mental illness and herbal therapies are potential alternatives and adjuncts for its treatment. Hesperidin is the major flavonoid isolated from cit- rus fruits which has neuroprotective, antioxidant and antidepressant activity. OBJECTIVES: We studied the effect of exposure to Hesperidin during pregnancy on postpartum antide- pressant-like effects in mice. METHODS: Twelve male and 40 female mice (28-30 gr) were randomly selected and after determina- tion of the pregnancy using vaginal plaque, allocated into 4 experimental groups. Group 1 was kept as control and groups 2-4 were i.p. injected with 0.1, 0.5 and 1 mg/kg of hesperidin on days of 5, 8, 11, 14 and 17 of pregnancy. The control group received i.p. injection of the saline on the same days. Following postpartum, forced swimming test (FST), tail suspension test (TST) and open field tests were used to eval- uate depressive-like antidepressant activity of hesperidin. At the end of the study, serum Malondialde- hyde (MDA), glutathione peroxidase (GPx), superoxide dismutase (SOD) and total antioxidant capacity (TAC) were determined. RESULTS: According to the results, administration of the different levels of the hesperidin (0.5 and 1 mg/ kg) at GD 5, 8, 11, 14 and 17 significantly decreased immobility time (S) in TST and FST on postpartum mice compared to control group (p ≤0.05). Pre-partum administration of hesperidin (0.1, 0.5 and 1 mg/kg) had no significant effect on OFT of control group (p >0.05). Administration of the hesperidin (0.5 and 1 mg/ kg) during the GD significantly decreased MDA levels on postpartum compared to control group (p ≤0.05). Also, pre-partum administration of the hesperidin (0.1, 0.5 and 1 mg/kg) significantly increased SOD and GPx levels on postpartum mice compared to control group (p ≤0.05). CONCLUSIONS: These results suggested pre-partum administration of hesperidin has antidepressant and antioxidant effect in postpartum mice.