Puerarin extracted from Radix puerariae has been shown to exert neuroprotective effects. However, it is still not known whether puerarin protects hippocampal neurons against cell death in pilocarpine-induced seizures. In this study, we found that pretreatment with puerarin significantly attenuated the neuronal death in the hippocampus of rats with pilocarpine-induced epilepsy. In addition, puerarin decreased the level of seizure-induced reactive oxygen species in mitochondria isolated from the rat hippocampi. Terminal deoxyuridine triphosphate nick-end labeling staining showed that puerarin exerted an anti-apoptotic effect on the neurons in the epileptic hippocampus. Western blot analysis showed that puerarin treatment significantly decreased the expression of Bax and increased the expression of Bcl-2. Moreover, puerarin treatment restored the altered mitochondrial membrane potential and cytochrome c release from the mitochondria in the epileptic hippocampi. Altogether, the findings of this study suggest that puerarin exerts a therapeutic effect on epilepsy-induced brain injury through antioxidant and anti-apoptotic mechanisms.