Objective This study was to investigate the role and potential molecular mechanism of ethyl pyruvate（ EP） on the damage of nervous function induced by middle cerebral artery occlusion（ MCAO）. Methods A total of 40 male sprague-dawley rats were randomly and averagely divided into 4 groups： sham operation group（ Sham）， middle cerebral artery occlusion group（ MCAO）， middle cerebral artery occlusion + 5 mg/kg EP group（ MCAO+5EP）， middle cerebral artery occlusion + 10 mg/kg EP group（ MCAO+10EP）. Nerve injury and repairment in rats were measured by nerve injury severity score（ mNSS） and rotation test. Expressions of brain derivied neurotrophic factor（ BDNF） and neuron grouthfactor (NGF)， Notch1 and Nuclear factor-kappa B（ NF-κB） signals were tested by Real-time quantitative PCR. Results Compared with MCAO group， EP with two dosages all significantly reduced mNSS score（ all P＜0.05）， increased the duration of rats in 15 rpm rotating shaft（ all P ＜ 0.05）， up-regulated the expressions of BDNF and NGF mRNA（ all P ＜ 0.05）， down-regulated the expressions of Notch1 and NF-κB mRNA（ all P＜ 0.05）. The effectiveness with 10 mg/kg EP was better. Conclusions 10 mg/kg EP has better neuroprotective effects on nerve protection， and its mechanism may be related to inhibition of Notch1 and NF-κB signals.