The liver as a vital body organ is adversely affected by hazardous chemicals and drugs. Paracetamol widely used as analgesic and antipyretic drug produces severe hepatotoxicity at high doses. Present study was designed to investigate the hepatoprotective activity of Polygonum perfoliatum L. used on folklore basis. Aqueous methanolic extract of the plant was prepared. Preliminary phytochemical and HPLC analyses were carried out to identify and quantify chemical constituents respectively. For hepatoprotective activity, Wistar rats were divided into six groups as normal control, standard (silymarin) control, negative control and extract treated groups i.e., 125, 250 and 500 mg/kg/day per oral. Paracetamol was administered orally, following seven days of previously stated therapy. Biochemical parameters of hepatotoxicity such as serum glutamic pyruvate transaminase (SGPT), serum glutamic oxaloacetate transaminase (SGOT), alkaline phosphatase (ALP) and total bilirubin were measured in all groups. Histopathological evaluation of liver was also carried out. Benzoic acid, chlorogenic acid, gallic acid, m-coumaric acid, quercetin and vitamin E were detected in the plant extract through HPLC. The hepatoprotective effect of 500 mg/kg/day therapy was more pronounced than 125 and 250 mg/kg dose. However, the effect of plant extract was less pronounced than standard silymarin therapy. It can be concluded that the plant extract possessed significant hepatoprotective activity that may be attributed to quercetin, benzoic acid, gallic acid and vitamin E present in it.