Objective To investigate the neuroprotective effect of clopidogrel on cerebral ischemiareperfusion injury in rats based on PI3K/Akt pathway. Methods Rat models of cerebral ischemia reperfusion were established and randomly divided into model group， clopidogrel group， LY294002 （PI3K/Akt pathway inhibitor） group and clopidogrel + LY294002 group， with 12 rats in each group， and another 12 SD rats were used as sham operation group. After grouping， all rats were scored for neurological deficit and blood was taken from caudal vein to execute the rats. Hematoxylin-eosin （HE） staining was used to detect the pathological changes of neurons in each group， the infarct size of brain tissue was measured by TTC staining， enzyme-linked immunosorbent assay （ELISA） was used to detect the levels of serum central nervous specific protein （S100β）， neuron specific enolase （NSE）， interleukin-6 （IL-6）， and tumor necrosis factor-α （TNF-α）， and the expression of PI3K/Akt pathway protein in brain tissue was detected by Western blotting. Results Compared with shamoperated group， neuron necrosis and nuclear contraction decreased in model group； neurological deficit score， cerebral infarction area， levels of serum S100β， NSE， IL-6 and TNF-α increased significantly （P ＜ 0.05），while p-PI3K/PI3K and p-Akt/Akt decreased significantly （P ＜ 0.05）. Compared with the model group， the pathological damage of neurons in clopidogrel group was alleviated； neurological deficit score， cerebral infarction area， levels of serum S100β， NSE， IL-6 and TNF-α decreased significantly （P ＜ 0.05）， while p-PI3K/PI3K and p-Akt/Akt increased significantly （P ＜ 0.05）. Neuronal pathological damage in LY294002 group was aggravated； neurological deficit score， cerebral infarction area， levels of serum S100β， NSE， IL-6 and TNF-α increased significantly （P＜ 0.05）， while p-PI3K/PI3K and p-Akt/Akt decreased significantly （P ＜ 0.05）. Compared with LY294002 group， the pathological damage of neurons in clopidogrel + LY294002 group was alleviated； the neurological deficit score， cerebral infarction area， levels of serum S100β， NSE， IL-6 and TNF-α decreased significantly （P＜ 0.05）， while p-PI3K/PI3K and p-Akt/Akt increased significantly （P ＜ 0.05）. Compared with clopidogrel group， neuropathological damage was aggravated in clopidogrel + LY294002 group； neurological deficit score， cerebral infarction area， levels of serum S100β， NSE， IL-6 and TNF-α increased significantly （P ＜ 0.05）， while p-PI3K/PI3K and p-Akt/Akt decreased significantly （P ＜ 0.05）. Conclusions Clopidogrel can alleviate cerebral ischemia-reperfusion injury and protect brain tissue by activating PI3K/Akt pathway in rats.