Coccinia grandis has been used in tribal populations of India both as food and medicine, but it has been not reported to be a neuroprotective agent yet. The present study was designed to evaluate the protective effects of Coccinia grandis leaf extract on diabetes induced brain damage of Wistar rats. This study reports the protective effect of methanolic leaf extract of Coccinia grandis against STZ induced diabetes in rats. Metformin (150mg/kg body wt.) was used as a reference drug. The enzymes of the polyol pathway and its related substrates were studied in the brain tissue. The effect of Coccinia on Cyclooxygenase (COX) and Prostaglandin peroxidise (PG) was also studied. Diabetes induced rats showed a significantly increased activity of Aldose reductase, Sorbitol dehydrogenase, Glucose-6-phosphodehydrogenase, whereas the decreased activity of Hexokinase. The content of Glucose, Sorbitol significantly increased in rat brain. Sodium potassium ATPase activity was also decreased in diabetic rats. COX, PG peroxidase was increased. Histological alternations were induced in the hippocampus of STZ treated diabetic rats. Oral administration of Coccinia leaf extract (200mg/kg) of body weight to diabetic rats for 21 days efficiently attenuated the parameters studied. A decreased activity of brain AR, sorbitol dehydrogenase, glucose-6-dehydrogenase was observed along with the increase in Hexokinase and Sodium potassium ATPase activity. It also showed decreased content of glucose and Sorbitol. Diabetes induced brain damage in the hippocampus and cerebral cortex was restored with Coccinia treatment. Decreased COX and PG peroxidase suggest its protection against inflammation. The current results suggest that Coccinia grandis leaf extract exerts the potential ability to reverse the progression of hyperglycemia and its concomitant induced brain damage.