Background: Spondias mombin L. (Anacardiaceae) is used in folk medicine in Nigeria for the treatment of hepatitis. Objective: This study comparatively evaluates the in vivo hepatotoprotective and antioxidant effects of Spondias mombin leaf (SML) and stem (SMS) methanolic extracts in rat’s model of hepatotoxicity. Materials and Methods: Acute hepatotoxicity was induced by administering CCl4 to forty-two Wistar rats divided into seven groups. After 48 hours rats were sacrificed and assayed for histological and biochemical indices of hepatotoxicity. Results: Treatment with CCL4 induced hepatocellular injury with significant (p<0.001) increase in the activities of ALT, AST, total bilirubin (TBIL) and conjugated bilirubin (CBIL) and a significant (p<0.001) decrease in total protein (TP) compared to the negative control. The plant extracts, SML 500 and 1000 mg/kg, significantly (p<0.001-0.05) deceased ALT, AST, TBIL, and CBIL. SMS extracts at 500 and 1000 mg/kg significantly (p<0.001-0.01) decreased ALT, AST, TBIL, and CBIL compared to the CCl4 treatment alone. The extracts showed dose-dependent significantly (p<0.001-0.05) increased glutathione, catalase, and sodium dismutase activities and significantly (p<0.001- 0.01) decreased thiobarbituric acid reactive substances (TBARS) relative to the CCl4 treatment alone. Both SML and SMS had no significant effect on body weight and haematological indices. The results suggest that the extracts have significant hepatoprotective effects on CCl4-induced liver injury. This effect may be in part due to ability of extracts to inhibit lipid peroxidation and up regulation of hepatic antioxidant enzymes. Conclusion: The results provide preliminary evidence supporting the potential benefit of SML and SMS for the treatment of xenobiotic-induced hepatotoxicity.