Background: There is an increasing incidence of liver failure and lack of effective drugs for liver diseases. Aim and Objective: This study identified the phytochemicals present in aqueous and ethanolic Bixa orellana L. leaf extracts and investigated the hepatoprotective activity against carbon tetrachloride (CCl 4 )-induced hepatotoxicity in mice. Specifically, the study compared serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and examined liver tissues histopathology. Materials and Methods: Aqueous and ethanolic B. orellana L. leaf extracts were prepared and screened for phytochemical contents. An oral dose of 500 mg/kg body weight was identified from toxicity test and administered to albino mice. Microscopic examination of the liver tissues assessed the extent of hepatic injury. Serum AST and ALT levels were compared using one-way analysis of variance with Bonferroni post hoc analysis at 5% level of significance using Stata/SE V12.0 software. Results: B. orellana L. leaves contained alkaloids, anthraquinones, sugars, and tannins. Aqueous and ethanolic leaf extracts of B. orellana L. did not show any toxicity up to 2000 mg/kg body weight oral dose in mice. Pre-treatment for 7 days before CCl 4 administration significantly prevented elevation of serum AST and ALT levels with histopathologic findings showing a protective effect on the hepatocytes. Conclusion: B. orellana L. leaves have potent hepatoprotective activity against oxidative damage.