Background and Purpose: Myocardial infarction (MI) is an irreversible damage caused by ischemia and hypoxia in coronary arteries accompanied with elevated levels of catecholamine, leading to the accumulation of free radicals. Our previous study discovered coumarin-derived imino sulfonates as a novel class of potential cardioprotective agents possessing strong anti-oxidative effect in cardimyocytes. Therefore, the identification of the compound with the highest cardioprotective activity, 5h, and the mechanism involved was necessary. Experimental Approach: As a kind of catecholamine, isoproterenol induces MI injury mimicking symptoms of MI patients in clinic. Cardiac function, nfarct area, histopathological changes were evaluated. The potential mechanism underlying such action of compound 5h was explored via transfection with adenovirus to downregulate Sirt1 in vitro, and by administration of Ex527, the specific inhibitor for Sirt1, in vivo. Key Results: Compound 5h exhibited strong cardioprotective actions in vivo and in vitro via improving cell survival, cardiac function and decreasing the cellular oxidative stress and cardiac infarct size against MI. Furthermore, compound 5h significantly enhanced cardiac expression of Sirt1, subsequently activating the Nrf2/NQO1 signaling pathway. However, adenovirus induced Sirt1 downregulation or Sirt1 specific inhibitor largely blocked such beneficial effects of 5h in vitro and in vivo, respectively. Conclusions and Implications: Our results demonstrated, for the first time, that the cardioprotective action of 5h against MI was mediated by reducing oxidative stress and apoptosis through the Sirt1/Nrf2 signaling pathway. Our findings proposed novel insights in the development and evaluation of coumarin-derived imino sulfonate compounds as epigenetics-targeted drug therapy for MI.