Empagliflozin (EMPA) reduces heart failure hospitalization and mortality. The benefit in terms of ventricular arrhythmia and contractility has not been explored. To determine the direct effects of EMPA on ventricular arrhythmia and cardiac contractility in an ex-vivo model of global ischemia-reperfusion (I/R). Langendorff-perfused rabbit hearts were subjected to 30 min of complete perfusion arrest and reperfusion. Either EMPA (1 μM) or normal saline (controls) was then infused into the perfusate in a randomized fashion. Ten minutes following drug infusion, calcium imaging was performed. At the end of each experiment, the heart was electrically stimulated 5 times to assess the inducibility of ventricular fibrillation (VF). In a separate series of experiments, left ventricular (LV) pressure and epicardial NADH fluorescence were simultaneously recorded. LV specimens were then collected for western blotting. Post-ischemia, EMPA treatment was associated with reduction in the induction of VF >10s (rate of induction: 16.7 ± 3.3% vs. 60 ± 8.7% in control hearts, p = 0.003), improvement of LV developed pressure (LVDP; 68.10 ± 9.02% vs. 47.61 ± 5.15% in controls, p = 0.03) and reduction of NADH fluorescence (87.42 ± 2.79% vs. 112.88 ± 2.27% in control hearts, p = 0.04) along with an increase in NAD+/NADH ratio (2.75 ± 0.55 vs. 1.09 ± 0.32 in the control group, p = 0.04) A higher calcium amplitude alternans threshold was also observed with EMPA-treatment (5.42 ± 0.1 Hz vs. 4.75 ± 0.1 Hz in controls, p = 0.006). Sodium-glucose co-transporter-2 (SGLT2) expression was not detected in LV tissues. EMPA treatment reduced ventricular arrhythmia vulnerability and mitigated contractile dysfunction in the global I/R model while improving calcium cycling and mitochondrial redox by SGLT2-independent mechanisms. In normoxic conditions, NADH is generated by the reduction of NAD+ in metabolic pathways by glucose oxidation and Krebs cycle. NADH is oxidized to NAD+ by ETC to produce ATP. ETC dysfunction during hypoxia (Red dotted arrow) is associated with the accumulation of NADH. Improvement of ETC function by EMPA (Blue solid arrow) leads to increase in NAD+/NADH ratio, improvement of contractile function, improvement of cytosolic calcium dynamics, and reduction of vulnerability to ventricular arrhythmias. Glu: Glucose, Pyr: Pyruvate, TCA cycle: Tricarboxylic acid cycle (Krebs cycle), ETC: Electron transport chain, EMPA: Empagliflozin, I/R: Ischemia-reperfusion, SR: Sarcoplasmic reticulum. Display omitted •Cardioprotective effects of Empagliflozin were evaluated in a model of global ischemia-reperfusion (I/R)•Empagliflozin increased contractility and decreased ventricular arrhythmia vulnerability•Improvements in mitochondrial redox state and cytosolic calcium dynamics were also noted with Empagliflozin treatment•In our Langendorff model, the cardioprotective effects of Empagliflozin were independent of SGLT2 inhibitory actions•These cardioprotective actions may explain the favorable effects of SGLT2i agents in heart failure which is independent of blood sugar control