This study aimed to investigate the protective effect of methanol extract of Sclerocarya birrea (S. birrea) stem bark on Doxorubicin (DOX) induced cardiotoxicity in rats. Tissue Malondialdehyde (MDA) level was increased in DOX treated group while activities of antioxidant maker enzymes; Catalase (CAT), Superoxide Dismutase (SOD) were significantly decreased. Cardiotoxicity was further confirmed by significant increase in the serum levels of cardiac markers; troponin, creatine kinase, aspartate transaminase and myoglobin in DOX treated group. Histological examinations show that S. birrea at 600 mg/kg have improved the heart structural abnormalities induced by DOX. This showed that the S. birrea stem bark extract had potential to prevent oxidative damage induced by DOX in the heart and could serve as novel adjuvant antioxidant therapy with chemotherapeutic agents.