Purpose <p>The purpose of the current study is to evaluate the role of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in the treatment of patients with diabetes with newly diagnosed acute myocardial infarction (AMI).</p> Methods <p>This multicenter, prospective, cohort study included 1161 patients with diabetes with newly diagnosed AMI. The primary endpoint events included rehospitalization for heart failure (HF) and major adverse cardiovascular events (MACEs). The secondary endpoint events were recurrent MI and cardiac death.</p> Results <p>Patients were categorized into the SGLT2i group and the non-SGLT2i group. During a median follow-up of 1.8 (1.5–2.3) years, the risk of hospitalization for HF (HR 0.58; 95% CI 0.36–0.94; <i>P</i> = 0.026) and MACEs (HR 0.59; 95% CI 0.40–0.86; <i>P</i> = 0.006) were lower in the SGLT2i group, with a similar trend observed for cardiac death (HR 0.51; 95% CI 0.27–0.99; <i>P</i> = 0.046). SGLT2i appears to be a better choice for all such patients. However, our research further found the above trends were observed mainly in the LVEF &lt; 50% subgroup. In addition, our study also revealed novel findings that the protective effect of SGLT2i was not altered by baseline levels of HbA1c in these patients, nor by different SGLT2i medications.</p> Conclusion <p>The outcomes of the current investigation suggest that SGLT2i is preferred as a hypoglycemic and cardiovascular protective drug for patients with diabetes with newly diagnosed AMI. It could improve cardiovascular outcomes, reducing the risk of rehospitalization for HF and MACEs, particularly in patients with reduced LVEF.</p> Trial registration <p>Role of SGLT2I in Patients with Myocardial Infarction, NCT06245980. <a href="https://clinicaltrials.gov/ct2/show/NCT06245980">https://clinicaltrials.gov/ct2/show/NCT06245980</a>. Retrospectively registered.</p> Graphical Abstract <p></p>