Oxidative stress is common mechanism during hypoxia that resulted to molecular alterations such as lipid peroxidation in cerebral cortex of mouse brain. Oxidative stress during hypoxia is due to depletion of antioxidant enzymes and reduced glutathione. Oxidative stress during hypoxia in cerebral cortex is due to depletion of antioxidant enzymes. Fisetin, a dietary flavonol, protects brain cells against oxidative stress in vitro. In addition, fisetin protects hepatocytes against oxidative stress by modulating the activity of antioxidant enzymes. Thus, It has been hypothesize that fisetin could protect cerebral cortex against oxidative stress in vivo. Aim of this study was to evaluate the antioxidant efficacy of fisetin against CoCl2-hypoxia in the mouse cerebral cortex in vivo. Fifteen days oral administration of CoCl2 to mice resulted in a significant increase in levels of reactive oxygen species (ROS) without altering serum aspartat transaminase (AST) and alanine transaminase (ALT), indicating no damage to liver. Increased levels of ROS resulted to increased level of lipid peroxidation. In addition decreased levels of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) activity and non-enzymatic antioxidant GSH further confirmed the CoCl2 induced oxidative stress in cerebral cortex of mice brain. Continuous treatment with fisetin (5 mg/kg) orally twice daily for 15 days significantly restore the antioxidant enzymes and GSH in cerebral cortex resulted to reduced level of ROS and LPO and offered almost complete protection. Fisetin has potential antioxidant against oxidative stress induced by CoCl2-hypoxia in the cerebral cortex of the mice brain.