AIM: The aim of this study was to investigate the antioxidant and hepatoprotective activity of ethanolic extract of the leaves of Polygonum glabrum in carbon tetrachloride (CCl4) induced hepatotoxicity in rats. METHODS: Rats were pretreated orally for 8 days with the ethanolic leaf extract of P. glabrum (200 and 400 mg/kg) and curcumin (100 mg/kg) as the standard prior to CCl4 (1ml/kg body weight, intraperitonial) intoxication. Hepatoprotective action was assessed based on the decrease in the levels of hepatic serum markers such as serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (ALP), total bilirubin (TB), direct bilirubin (DB) and increased total protein levels. Further, liver tissue was subjected to histopathological studies and also assessed for oxidative parameters such as malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) levels. RESULTS: Pretreatment with curcumin and ethanolic leaf extract of P. glabrum significantly inhibited CCl4 induced increase of SGPT, SGOT, ALP, TB and DB levels in serum and decrease in total protein levels. Significant and dose dependent increase in the hepatic SOD, CAT, GSH activities along with decrease in MDA levels were observed in the curcumin and P. glabrum extract pretreated animals. The liver histological examination also showed lowered damage in the extract pretreated animals. CONCLUSION: The ethanolic leaf extract of P. glabrum exhibited significant hepatoprotective effect which could be attributed to its antioxidant activity.