Objective To investigate the protective effect of tetrahydroxystilbene glucoside (TSG) on cerebral ischemia/ reperfusion (I/ R) injury in mice. Methods One-hundred mice were divided randomly into five groups of 20mice each: sham, I/ R group, and low TSG (3 mg/ kg), medium TSG (6 mg/ kg) and high TSG (12 mg/ kg) groups. Themice underwent cerebral ischemia for 2 h by ligation of bilateral common carotid arteries, and were sacrificed 24 h afterreperfusion. Pathology of the brain tissues was assessed by hematoxylin and eosin (H&E) staining. Reactive oxygen species(ROS) levels in brain tissues were measured by dihydroethidium staining and electron spin resonance spectroscopy.Expression of the proteins of NADPH oxidase (NOX) 4 and cleaved caspase (CC)-3 and CC-9 in brain tissues weredetected by Western blot. Results Compared with the sham group, there was deformation and swelling of neurons,pyknosis and anachromasis of nuclei as well as shrunken cell bodies in the I/ R group. ROS levels were increasedsignificantly, and expression of NOX4, CC-3 and CC-9 was up-regulated significantly in the I/ R group. Compared with theI/ R group, TSG expression reduced markedly the pathological damages in brain tissues after cerebral I/ R. TSG downregulatedthe protein level of NOX4 significantly according to the Western blot. Dihydroethidium staining indicated that TSGdecreased ROS levels and inhibited the activity of CC-3 and CC-9 in the ischemic cortex after reperfusion. Conclusions TSG has neuroprotective effects on cerebral I/ R injury in mice. TSG may be associated with inhibiting expression of NOX4protein, thereby reducing ROS levels, and inhibiting overexpression of the apoptosis-related proteins CC-3 and CC-9.