In spite of the advances in the treatment of ischemic heart diseases, acute myocardial infarction (AMI) remains the leading cause of death in the developed countries. Myocardial ischemia reperfusion (I/R) injury occurs during the invasive treatments such as, thrombolysis, angioplasty, coronary by-pass and heart transplantation. The aim of this research is to clarify and compare the protective effects of Apelin, Amlodipine (long-acting dihydropyridine-type (DHP) calcium channel blocker) and Anakinra (Kineret-Interleukin-1 Receptor Antagonist) on ischemia- reperfusion injury in myocardium of experimental animals. Design: A total number of 50 healthy adult male albino rats were used to study and compare the effect of Apelin-13 (injected intraperitoneally at a dose of 1 µg/kg 15 min before reperfusion began), Amlodipine (administered at a dose of 1 mg /kg body weight daily by oral route for 7 days) and Anakinra (a single intravenous shot of 2mg/kg body weight) on preventing myocardial reperfusion injury in experimental animals. Results: The results of this study showed that in Apelin, Amlodipine and Anakinra treated groups, the mean values of all test parameters were significantly lower than ischemia /reperfusion group(p <0.001). In Anakinra treated group, the mean values for all parameters were found to be significantly lower when compared with that Apelin and Amlodipine treated groups. In addition, Infraction mass expressed as percentage of the left ventricle weight was found to be non-significantly changed between Anakinra treated group and Ischemic Control group; moreover, on comparing Apelin with Amlodipine treated groups, no significant changes were found. Conclusion: The results of this study suggest that administration of Apelin, Amlodipine and Anakinra prior to myocardial reperfusion reduces infarct size and markers of infarction in experimental ischemia/reperfusion injury with highest efficacy of Anakinra (Interleukin-1 Receptor Antagonist) more than Apelin and Amlodipine. Thus, they may represent a treatment option in myocardial infarction prior to revascularization.