Background: Myocardial infarction (MI) is a necrosis of cardiomyocytes due to prolonged myocardial ischemia, the injured heart characterized by activation of the renin-angiotensin system (RAS). The cardiac effect of enalapril and losartan was determined in Isoproterenol (ISO) induced MI rat model. Methods: Twenty-four adult male rats were randomly divided into four groups of six rats each, Group-I- Normal rats, group II-ISO (150 mg/kg once daily for two successive days), Group-III-Enalapril pretreated, and Group-IV-Losartan pretreated rats. Enalapril and losartan were given by gavage at dose 10 mg/kg and 30 mg/kg, respectively the treatment started 3 days before ISO injection and continue for 5 days after 2nd ISO dose. Results: ISO-induced group showed significant increase in the cardiac enzymes lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB), accompanied with marked decrease in the catalase (CAT) and glutathione (GSH) and Bcl2. Both enalapril and losartan induce significant reduction of cardiac enzymes and systolic blood pressure and improve oxidative stress which confirmed by reduction of Malondialdehyde (MDA) and elevation of antioxidant enzymes and markedly upregulated the expression of Bcl2, Nrf-2 and HO-1. Moreover, Both enalapril and losartan reversed the histopathological changes induce by ISO and thus exhibits its cardioprotective activity. Moreover, treated rats partially minimize myocardial necrosis and interstitial edema. In conclusion: Enalapril and losartan ameliorates oxidative stress, inhibit apoptosis and improve cardiac dysfunction by alteration of Nrf2/HO-1 signaling pathway. It also reduces cardiac enzymes and improves blood pressure without affection of serum K on short term therapy in MI.