In the present study, we investigated effects of the dried, hot-water extract of Cordyceps militaris (CME) and its major metabolite (cordycepin) against ischemic damage. The repeated treatment with CME protected hippocampal CA1 pyramidal neurons from ischemic damage in gerbils. The treatment with CME or cordycepin in gerbils reduced 4-hydroxy-2-nonenal (a marker of lipid peroxidation) immunoreactivity and levels in the ischemic CA1 region. Glial fibrillary acidic protein immunoreactive astrocytes and ionized calcium-binding adapter molecule 1 immunoreactive microglia in the vehicle-treated ischemic group were activated in the CA1 region 4 days after ischemia/reperfusion, whereas in the CME- or cordycepin-treated ischemic group, their activation was significantly decreased. These results suggest that the repeated treatment with CME protects against neuronal damage from ischemia/reperfusion by reducing oxidative damage.