Cerebral hypoperfusion (CH) is a contributing factor to impairments observed in individuals diagnosed with Alzheimer's disease, vascular dementia and the elderly population. CH-induced brain damage is closely associated with oxidative stress (OS), manifested through disturbed prooxidative/antioxidative balance (PAB) within cells. Elevated levels of xanthine oxidase (XOD) are identified as a potential causal factor of OS, ultimately culminating in cell death. We aimed to investigate the protective effects of the hormone progesterone (P4) against CH‐induced OS and neurodegenerative pathologies in rat prefrontal cortex (PFC). Adult male Wistar rats were divided into three groups: (I) animals subjected to permanent bilateral occlusion of common carotid arteries (2VO) treated with vehicle (commercial flax oil, 1 mg/kg/day), (II) animals subjected to 2VO treated with P4 dissolved in vehicle (1.7 mg/kg/day) and (III) animals subjected to sham-operation treated with vehicle. Following 7 days of subcutaneous treatments, animals were sacrificed. Levels of PAB and XOD were estimated by assays, while the level of cell death was determined by Fluoro-Jade C staining (FJC). The results revealed that P4 administration moderated CH-induced impairments by decreasing PAB levels and diminishing levels of FJC-positive cells. Interestingly, XOD levels remained unchanged through experiment suggesting that some other source of OS was present in the cell. The findings suggest that P4 has the potential to mitigate the prooxidant state induced by CH and the subsequent alterations in PFC. While this hormone shows promise as a viable candidate for treating CH, the specific mechanisms underlying its actions still require further exploration and understanding.