Present study was undertaken to evaluate the protective effect of 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose (PGG) against transient global ischemia/reperfusion (I/R)-induced brain injury in rats. Sixty minutes of global ischemia, followed by 24h of reperfusion caused significant alterations in cognition and memory (p<0.01), significant deterioration of motor coordination, grip strength, and limb tone (P<0.01) associated with neurological deficit. In addition, significant decrease in catalase (P<0.01), and superoxide dismutase (SOD) (P<0.01) activities, increase in lipid peroxidation (P<0.01), depletion of reduced glutathione (GSH) (P<0.01), and increase in brain volume (P<0.01) was observed. Additionally, I/R insult has aggravated the cerebral infarct formation (P<0.01), and the histopathology of brain showed congestion of blood vessels, edema of brain parenchyma, leukocyte infiltration as signs of neuroinflammation, and necrosis of brain tissue. Interestingly, pre-treatment with quercetin (20mg/kg, i.p.), and PGG (5 and 10mg/kg, i.p.) for 7 days showed significant, and dose dependent protection against I/R-induced brain injury by alleviating all the behavioral, neurological, morphological, and histological changes induced by I/R. Besides, PGG is a well-known antioxidant, and its protective effect against I/R-induced brain injury is thought to be due to its potent antioxidant property.