Cardiovascular disease is the world's leading cause of death, killing 17 to 19 million people each year. The usage of traditional drugs was influenced by the need for effective medications for the treatment of cardiovascular disease without side effects. The current study investigated the cardio-protective effects of Adansonia digitata leaf extract on doxorubicin-mediated cardiotoxicity in laboratory rats. Thirty-five albino rats were divided into five groups, each consisting of seven rats. Group 1 was given filtered water as a control, while Group 2 was given saline and doxorubicin, Group 3 received doxorubicin and Vitamin E, and Groups IV and V were myocardial oxidative animals treated with Adansonia digitata leaf extract (150 and 300 mg/kg/wt) for two weeks. After the rats were sacrificed, their hearts were collected and homogenized for biochemical assays. The results on the activities of creatinine kinase (CK), lactate dehydrogenase (LDH), aspartate amino transferase (AST), nitric oxide synthase (NOS), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde were determined. Histopathology examination was used in addition to assays to validate myocardial damage. In comparison to the control group, rats provided doxorubicin showed a significant increase in the activities of cardiac marker enzymes (CK, LDH, and AST), as well as a significant increase in malondialdehyde concentration with a concomitant decrease in antioxidant enzymes (SOD, CAT, and NOS), implying cardiotoxicity. In rats with doxorubicin-induced myocardial infection, pretreatment with Adansonia digitata leaf extract reduced myocardial damage, these biochemical results were confirmed by histopathology. Finally, the new study demonstrates that Adansonia digitata has cardioprotective properties.