Epilepsy is a severe and chronic neurological disease. Edaravone is an effective free radical scavenger and has been reported to prevent neuronal loss induced by Kainate (KA). However, the molecular mechanisms by which edaravone inhibits KA-induced neuron injury remain elusive. Seventy adult male Wistar rats were randomly divided into 7 groups. For KA treatment, Kainate (4 μg/kg) were administrated in the right hippocampus CA3 region with sereotactic technique. And for edaravone treatment, the rats were intraperitoneal injection with edaravone (10 mg kg - 1 d – 1). All rats were sacrificed on the seven day after the injection of KA. Histological changes of the hippocampus, CA1, CA3 and CA4 were observed under thionine staining. Histological changes of CA1 and CA3 were divided into the following 4 grades (histological grade,HG) under light microscope. The release of inflammatory cytokines was measured by ELISA assay. The inflammatory proteins and Nrf2 and HO-1 expression were determined by quantitative real time PCR (qRT-PCR) and Western blots analysis. Treatment with edaravone increased the neuronal density and decreased the neuronal damage degree in the CA1, CA3 subfield induced by KA. Besides, edaravone reduced the downregulation of the mRNA and protein expression levels of Nrf2 and HO-1 induced by KA. Moreover, edaravone decreased the levels of NF-κB (P65) and proinflammatory cytokines TNF-α, IL-1β and IL-6 and the inflammatory proteins expression levels, HMGB1, nNOS, iNOS and eNOS in the hippocampus. However, introduction of Nrf2-siRNA and HO-1 inhibitor (Znpp) reversed the effects of edaravone on KA-injected rats. Edaravone can protect hippocampal neurons from damage in KA-induced epilepsy rats through Nrf2/HO-1 pathway.