English Cyclophosphamide chemotherapeutic agent, it's used associated with multiorgan toxicity including the heart. Melatonin and cyanocobalamin possess cardiac-protective properties. This study was designed to evaluate the prophylactic effects of melatonin and cyanocobalamin. Fifty adult male rats have used in the study, divided into five groups each containing ten rats, melatonin, and cyanocobalamin were given orally for seven consecutive days before injection of (150 mg/kg) of cyclophosphamide on day seven. Group I: Control group, in which rats were intraperitoneally injected with (1 ml/kg/day) of normal saline. Group II: Rats were intraperitoneally injected with a single dose of cyclophosphamide. Group III: Rats were given orally melatonin at a dose (1 mg/kg/day) and cyclophosphamide. Group IV: Rats were given orally cyanocobalamin at a dose (0.1 mg/kg/day) and cyclophosphamide. Group V: Rats were administered orally a mixture of melatonin at a dose (1 mg/kg/day) and cyanocobalamin at a dose (0.1 mg/kg/day) and cyclophosphamide. On day eight rats were sacrificed, serum and heart extracted for malondialdehyde, interleukin-1 beta, and troponin I measurement, furthermore cardiac immunohistochemical study was performed. It was found that both melatonin and cyanocobalamin significantly (P<0.05) decrease serum levels of malondialdehyde, interleukin-1 beta, and troponin I in comparison with group II and improve immunohistochemical changes in cardiac tissue when compared with the group treated by cyclophosphamide only (group II).