ABSTRACT: Objective:To evaluate the antioxidant and cardioprotective activities of stem bark extract and solvent fractions of Croton macrostachyus on cyclophosphamide-induced cardiotoxicity in rats. Materials and Methods. DPPH free radical scavenging assay method was used to determine antioxidant activity whereas Sprague-Dawley rats were used to evaluate the cardioprotective activity. Except for the normal control, all groups were subjected to cyclophosphamide (200?mg/kg, i.p.) toxicity on the first day. Enalapril at 10?mg/kg was used as a reference. The hydromethanolic crude extract (100, 200, and 400?mg/kg) and aqueous and ethyl acetate fractions (100 and 200?mg/kg, each) were administered for 10 days. The cardioprotective activities were evaluated using cardiac biomarkers such as Troponin I, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total cholesterol (TC), triglyceride (TG), and histopathological studies of heart tissue. Results:Crude extract and ethyl acetate and aqueous fractions exhibited free radical scavenging activities at IC50 of 594??g/mL, 419??g/mL, and 716??g/mL, respectively. Crude extract at 400?mg/kg decreased the levels of troponin, AST, ALT, and ALP to 0.29?±?0.06?ng/mL, 103.00?±?7.63?U/L, 99.80?±?6.18?U/L, and 108.80?±?8.81?U/L, respectively. In addition, ethyl acetate fraction at 200?mg/kg decreased the levels of troponin, AST, ALT, and ALP to 0.22?±?0.02?ng/mL, 137.00?±?14.30?U/L, 90.33?±?6.13?U/L, and 166.67?±?13.50?U/L, respectively, compared with the cyclophosphamide control group. Conclusions:Croton macrostachyus possesses cardioprotective activities and it could be a possible source of treatment for cardiotoxicity induced by cyclophosphamide.