Brain Erythropoietin (EPO), an important neurotrophic factor and neuroprotective factor, was found to be associated with aging. Studies found EPO expression was significantly decreased in the hippocampus of aging rat compared with that of the youth. But mechanisms of the decline of the brain EPO during aging remain unclear. The present study utilized a d-galactose (d-gal)-induced aging model in which the inducement of aging was mainly oxidative injury, to explore underlying mechanisms for the decline of brain EPO in aging rats. d-gal-induced aging rats (2 months) were simulated by subcutaneously injecting with d-gal at doses of 50 mg·kg− 1, 150 mg·kg− 1 and 250 mg·kg− 1 daily for 8 weeks while the control group received vehicle only. These groups were all compared with the aging rats (24 months) which had received no other treatment. The cognitive impairment was assessed using Morris water maze (MWM) in the prepared models, and the amount of β-galactosidase, the lipid peroxidation product malondialdehyde (MDA) level and the superoxide dismutase (SOD) activity in the hippocampus was examined by assay kits. The levels of EPO, EPOR, p-JAK2 and hypoxia-inducible factor-2α (HIF-2α) in the hippocampus were detected by western blot. Additionally, the correlation coefficient between EPO/EPOR expression and MDA level was analyzed. The MWM test showed that compared to control group, the escape latency was significantly extended and the times of crossing the platform was decreased at the doses of 150 mg·kg− 1 and 250 mg·kg− 1 (p < 0.05). Also, the amount of β-galactosidase and the MDA level in the hippocampus were significantly increased but the SOD activity was significantly decreased (p < 0.05, 0.01 and 0.01, respectively). Similar to aging rats, the expressions of EPO, EPOR, p-JAK2, and HIF-2αin the brain of d-gal-treated rats were significantly decreased (p < 0.05) at 150 mg·kg− 1 and 250 mg·kg− 1. Interestingly, negative correlations were found between EPOR (r = − 0.699, p < 0.01), EPO (r = − 0.701, p < 0.01) and the MDA level. These results indicated that aging could result in the decline of EPO in the hippocampus and oxidative stress might be the main reason for the decline of brain EPO in aging rats, involved with the decrease of HIF-2α stability.