Vernonia amygdalina Del. (Family Compositae) is used in Nigerian folk medicine as a tonic and remedy against constipation, fever, high blood pressure, and many infectious diseases. We have evaluated the hepatoprotective and antioxidant effects of an aqueous extract of V. amygdalina leaves against acetaminophen-induced hepatotoxicity and oxidative stress in mice in vivo. Activities of liver marker enzymes in serum (glutamate-oxaloacetate transaminase, glutamate-pyruvate transaminase, lactate dehydrogenase, and alkaline phosphatase) and bilirubin levels were determined colorimetrically, while catalase activity, lipid peroxidation products, thiobarbituric acid-reactive substances (TBARS), iron, and total protein concentrations were measured in liver homogenate. Acetaminophen challenge (300 mg/kg, i.p) for 7 days caused significant (P < .01) increases in the levels of bilirubin, liver enzymes, TBARS, and iron, while catalase activity and total protein level were reduced significantly (P < .01). Preadministration of V. amygdalina resulted in a dose-dependent (50-100 mg/kg) reversal of acetaminophen-induced alterations of all the liver function parameters by 51.9-84.9%. Suppression of acetaminophen-induced lipid peroxidation and oxidative stress by the extract was also dose-dependent (50-100 mg/kg). The results of this study suggest that V. amygdalina elicits hepatoprotectivity through antioxidant activity on acetaminophen-induced hepatic damage in mice.