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The liver is the center for drug and xenobiotic metabolism, which is influenced most with medication/xenobiotic, mediated toxic activity. This study was designed to investigate the effect of aqueous leaf extract of Vernonia amygdalina on acetaminophen- induced liver damage. 25 adult Wistar rats were used for the experiment. The experimental animals were randomly divided into five groups, each group comprised of 5 rats. In this study, group 1 rats were administered water throughout the duration of the experiment. Group-2 rats were administered acetaminophen (3000mg/kg b/w) as a single application. Group-3, 4 and 5 rats were administered acetaminophen (3000mg/kg b/w) and in addition received 50mg/kg Vernonia amygdalina, 100mg/kg b/w of Vernonia amygdalina and 200mg/kg of Silymarin daily for 14 days. The liver, kidney and serum antioxidant enzymes (Catalase, Superoxide Dismutase and glutathione) were assessed. Induction of acetaminophen (3000mg/kg) showed significant (p<0.05) decreased activities of antioxidant enzymes (Catalase, Superoxide Dismutase and glutathione) in group 2(acetaminophen 3000mg/kg) alone when compared to the normal control (group 1). The administration of aqueous extract of Vernonia amygdalina and Silymarin (significantly protected and restored liver, kidney and serum decreased in activities of antioxidant enzymes (Catalase, Superoxide Dismutase and glutathione) caused by acetaminophen (groups 3, 4 and 5) when compared to the untreated group (group 2). The study had demonstrated that aqueous leaf extract of Vernonia amygdalina ameliorate liver and kidney of male albino Wistar rats against acetaminophen induced toxicity and modulates the adverse effects on antioxidant enzymes.