Methanolic extract of Phyllanthus-polyphyllus was evaluated for hepatoprotective and antioxidant activities in rats. The plant extract (200 and 300 mg/kg, p.o.) showed a remarkable hepatoprotective and antioxidant activity against acetaminophen induced hepatotoxicity as judged from the serum marker enzymes and antioxidant levels in liver tissues. Acetaminophen induced a significant rise in aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), total bilirubin, gamma glutamate transpeptidase (GGTP), lipid peroxidase (LPO) with a reduction of total protein, superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and glutathione S-transferase (GST). Treatment of rats with different doses of plant extract (200 and 300 mg/kg) significantly (P<0.001) altered serum marker enzymes and antioxidant levels to near normal against acetaminophen treated rats. The activity of the extract at dose of 300 mg/kg was comparable to the standard drug, silymarin (50 mg/kg, p.o.). Histopathological changes of liver sample were compared with respective control. Results indicate the hepatoprotective and antioxidant properties of Phyllanthus polyphyllus against acetaminophen-induced hepatotoxicity in rats.