〔Abstract〕 Objective To investigate the role and mechanisms of empagliflozin(EMPA) on myocardial ischemia/reperfusion(MI/R) injury. Methods Forty male SD rats were randomly divided into Control group, MI/R group,2. 5 μmol/L EMPA combined with MI/R group(EMPA + MI/R) as well as EMPA and 10 μmol/L SIRT1 inhibitor EX527 combined with MI/R group(EMPA + EX527 + MI/R). Cardiac function, myocardial fiber morphology and infarct size were detected. The content of malonaldehyde(MDA), the activities of superoxide dismutase(SOD)and succinodehydrogenase(SDH) in myocardium were determined by ELISA. The protein expressions of Cytochrome c, Cleaved caspase-3, SOD2, gp91phoxand SIRT1 were observed by Western blot. The ROS level was detected by DHE staining.Results Compared with Control group, MI/R group manifested the decreased cardiac function and myocardial fiber rupture. Myocardial infarction area, the expressions of Cytochrome c, Cleaved caspase-3 and gp91phox, as well as the MDA content and ROS level increased, while decreased the activities of SOD and SDH, and the expressions of SOD2 and SIRT1. Compared with MI/R group, EMPA + MI/R group improved cardiac function and inhibited myocardial fiber rupture, myocardial infarction area, the expressions of Cytochrome c and Cleaved caspase-3. The expression of gp91phox, the MDA content and ROS level were also downregulated,while the activities of SOD and SDH and the expressions of SOD2 and SIRT1 were upregulated. However, the protective effects of EMPA on MI/R heart were blocked by EX527.Conclusion EMPA alleviates MI/R injury by inhibiting mitochondrial oxidative stress and apoptosisviaactivating SIRT1.