Aim To explore whether 5-lipoxygenase inhibitor zileuton attenuates neuroinflammation and brain damage via modulating ERK1/2 signaling path-way in rats of cerebral ischemia, and further investigate the possible mechanisms. Methods Sprague-Dawley rats underwent the cerebral ischemic injury by the su-ture occlusion model, and were randomly divided into sham operation, MCAO, zileuton-treated and PD98059 groups. Neurological deficit scores, cerebral infarct volume, and cerebral water content were measured, myeloperoxidase ( MPO ) activities in rat brain were measured as an index of neutrophil infiltration;content of TNF-α in blood was determined by the method of ELISA;expression of p-ERK1/2 and t-ERK1/2 in rat brain were detected by Western blot. Results Zileu-ton reduced neurological deficit scores, cerebral infarct volume, cerebral water content, MPO activity and TNF-α content, all of which were abolished by PD98059 administration. Zileuton up-regulated the ex-pression of p-ERK1/2 , which was inhibited by PD98059 administration. Conclusions Zileuton at-tenuates neuroinflammation and ischemic brain damage through the activation of ERK1/2 signaling pathway.