Cordymin is a peptide purified from the medicinal mushroom Cordyceps sinensis. The present study investigated the effects of Cordymin in prevention of focal cerebral ischemic/reperfusion (IR) injury. The right middle cerebral artery occlusion model was used in the study. The effects of Cordymin on mortality rate, neurobehavior, grip strength, glutathione content, lipid Peroxidation, glutathione peroxidase activity, glutathione reductase activity, catalase activity, Na(+)K(+)ATPase activity glutathione S transferase activity and on the regulation of C3 and C4 protein level, polymorphonuclear cells, interleukin-1β and tumor necrosis factor-α in a rat model were studied respectively. Treatment (orally) of Cordymin significantly boosted the defense mechanism against cerebral ischemia by increasing antioxidants activity related to lesion pathogenesis. Restoration of the antioxidant homeostasis in the brain after reperfusion may have helped the brain recover from ischemic injury. Moreover, Cordymin significantly inhibited infiltration of polymorphonuclear cells and IR-induced up-regulation of the brain production of C3 protein level, interleukin-1β and tumor necrosis factor-α. Cordymin significantly improved the outcome in rats after cerebral ischemia and reperfusion in terms of neurobehavioral function. Our findings suggest that cordymin have a neuroprotective effect in the ischemic brain, which is due to the inhibition of inflammation and increase of antioxidants activity related to lesion pathogenesis. Cordymin can be used as potential preventive agent against cerebral ischemia-reperfusion injury.