Background: Recent clinical trials have shown that an SGLT2 inhibitor improved both cardiac and renal outcomes in patients with type 2 diabetes mellitus (T2DM), but the mechanisms remain unclear. We hypothesized that inhibition of oxidative stress plays a role in reduction of mortality and acute kidney injury (AKI) after myocardial infarction (MI) in T2DM. Methods and Results: MI was induced in T2DM rats (OLETF) and control rats (LETO). Treatment with empagliflozin or canagliflozin for 14 days before MI reduced blood glucose levels and increased blood β -hydroxybutyrate (βOHB) levels in OLETF. The survival rate at 48 hr after MI was significantly lower in OLETF than in LETO (40% vs 84%), and empagliflozin significantly improved the survival rate to 70% in OLETF, though sizes of MI were comparable. Reduction of ATP level in the non-infarcted myocardium at 12 hr after MI in OLETF compared with that in LETO was prevented by empagliflozin. Myocardial Mn-SOD was increased and lipid peroxidation was suppressed by empagliflozin in OLETF after MI. Administration of β-OHB (8.0 mmol/kg/day, 7 days) partially mimicked the effects of empagliflozin in OLETF. MI significantly increased NGAL and KIM-1 protein levels in the kidney at 12 hr after MI in OLETF but not in LETO. Levels of lipid peroxides, NADPH oxidase (NOX)2 protein and NOX4 protein after MI were higher in OLETF than in LETO. Treatment with either canagliflozin or empaglifozin suppressed MI-induced renal expression of NGAL and KIM-1 in OLETF together with reductions in lipid peroxides and NOX proteins in the kidney. Pre-incubation with β -OHB attenuated angiotensin II-induced upregulation of NOX4 in NRK-52E cells. Conclusions: The findings suggest that treatment with an SGLT2 inhibitor prevents DM-induced increase in post-MI mortality and AKI possibly by β -OHB-mediated reduction of oxidative stress in T2DM.