• Hypothyroidism is associated with depressive symptoms. • Swimming exercise for 4 weeks alleviated depressive behavior in hypothyroid rats. • The enhanced irisin/BDNF axis activity following moderate aerobic exercise was positively correlated with climbing time in forced swimming test and with brain serotonergic system activity. • It is concluded that moderate aerobic exercise alleviated hypothyroidism-associated depression via increased BDNF expression. : The prevalence of depression with hypothyroidism is high. : To study the ability of aerobic exercise to improve hypothyroidism associated depression and to explore the underlying mechanisms. 21 adult male rats, allocated in three groups; Euthyroid, Hypothyroid (oral propyl-thiouracil for 45 days), Exercise-treated hypothyroid group (30 minutes, swimming, 4 weeks). Forced swim test and histopathological brain examination were performed. Serum free T3, T4, TSH, irisin, brain neurochemical, oxidant-antioxidant and apoptotic markers were measured . : Swimming exercise increased serum T3, T4, climbing and swimming times, brain serotonin, BDNF expression, glutathione peroxidase, antiapoptotic Bcl-2 and serum irisin levels and decreased TSH, immobility time, MDA, BAX/Bcl-2 ratio. Climbing time was positively correlated with BDNF, serotonin and T3. : Moderate aerobic exercise alleviated hypothyroidism-associated depression, via increased BDNF expression, which enhances hippocampal neurogenesis, serotonergic system activity and combat neuronal apoptosis.