Background Nuclear factor (erythroid-derived 2)-like-2 (NEFL2/Nrf2) is an inducible transcription factor that is crucial to fight against stress caused by various means (i.e. oxidative or xenobiotic stresses). While the Nrf2 has a negligible role on regulating the basal transcription of antioxidant/cytoprotective genes, its activation in response to stress is indispensable. Here, we hypothesize that augmentation of myocardial Nrf2, through transgene expression, will protect the myocardium from isoproterenol-induced pathological remodeling. Methods Cardiac specific Nrf2 transgenic (Nrf2-Tg) and non-transgenic (NTg) litter mates in the C57/BL6 background were subjected to isoproterenol (ISO) treatment (50-mg/kg bw/day, for 7 days), and assessed the myocardial structure, function (Echocardiography) and Nrf2-dependent defense mechanisms. Results Severe infarction and fibrosis along with increased inflammation leading to myocardial dysfunction in NTg mice exposed to ISO, but the Nrf2-TG hearts were found to be resistant to ISO insult. Suppression of infarction and protection of myocardial structure and function in the Nrf2-Tg mice could be attributed to a pro-reductive condition displayed in these hearts. In particular, ISO administration resulted in an excessive generation of reactive oxygen species and oxidation of proteins along with significant downregulation of antioxidant genes and their proteins lead to myocardial damage in NTg mice. Of note, myocardium of ISO-treated TG mice displayed significantly reduced protein oxidation (p Conclusion Thus, we conclude that a modest trans-activation of the global antioxidant defense system through genetic or non-pharmacological approaches might have therapeutic potential than either targeting single or combinations of antioxidant(s) to protect the myocardium in response to oxidative stress.