Background and objective <p>Sepsis is a major cause of mortality, particularly in patients with myocardial injury. The objective of this study was to evaluate the impact of dexmedetomidine, propofol, and midazolam on mortality and various outcomes in this population.</p> Methods <p>A retrospective cohort study was performed using the eICU database, encompassing 2,171 septic patients with myocardial injury. Patients were categorized into single- and multiple-sedative groups. The primary endpoint was 100-day mortality, with secondary endpoints encompassing hospital stay, intensive care unit (ICU) stay, mechanical ventilation (MV), and dialysis. Statistical analysis was conducted using Cox regression, Kaplan-Meier curves, and propensity score matching.</p> Results <p>Among 2,171 patients, dexmedetomidine was associated with lower 100-day mortality in patients with APACHE IV scores &lt; 78.9, particularly in specific subgroups. In patients with APACHE IV scores ≥ 78.9, dexmedetomidine provided no mortality advantage over propofol. Midazolam was linked to higher mortality across all score ranges, and its combination with propofol resulted in worse outcomes compared to dexmedetomidine-propofol. No significant differences were found in hospital stay, ICU stay, or MV rates between the groups.</p> Conclusion <p>Dexmedetomidine improves prognosis in septic patients with myocardial injury, particularly in those with lower severity of illness, highlighting its potential as a preferred sedative choice in this population.</p>