Oxidative stress is a common pathological condition associated with drug-induced hepatotoxicity. This study investigated Spondias mombin L. aqueous leaf extract on reactive oxygen species and acetaminophen-mediated oxidative onslaught in rats' hepatocytes. Hepatotoxic rats were orally administered with the extract and vitamin C for 4 weeks. The extract dose-dependently scavenged DPPH, hydrogen peroxide and hydroxyl radicals, with IC50 values of 0.13, 0.66, and 0.64 mg/mL, and corresponding % inhibitions of 89, 80, and 90%, respectively at 1.0 mg/mL. Ferric ion was also significantly reduced. The marked (p<0.05) increases in the activities of alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase were reduced following treatment with the extract. The extract also significantly (p<0.05) induced the activities of antioxidant enzymes. These inductions reversed the acetaminophen-enhanced reduction in the specific activities of these enzymes as well as attenuated the observed elevated concentrations of autooxidized products and rived DNA in the acetaminophen-intoxicated animals. The observed effects competed with those of vitamin C and are suggestive of hepatoprotective and antioxidative attributes of the extract. Overall, the data from the present findings suggest that S. Mombin aqueous leaf extract is capable of ameliorating acetaminophen-mediated oxidative hepatic damage via enhancement of antioxidant defense systems.