Purpose <p>Polyethylene glycol (PEG) is commonly administered in acute myocardial infarction (AMI) cases, though its clinical efficacy remains unclear. This study investigated whether PEG treatment enhances survival outcomes in AMI patients.</p> Methods <p>This retrospective study analyzed data from the American Medical Information Mart for Intensive Care (MIMIC)-IV database, examining critically ill patients with AMI. The exposure was defined as PEG administration during hospitalization. The primary endpoints were 7-day and in-hospital all-cause mortality. External validation was performed using the eICU 2.0 database.</p> Results <p>The study included 2422 participants before propensity score matching (PSM) and 1730 after matching. Multivariate Cox regression analysis prior to PSM revealed that PEG administration significantly lowered 7-day (HR = 0.247, 95% CI 0.179–0.341, <i>p</i> &lt; 0.001) and in-hospital (HR = 0.422, 95% CI 0.347–0.512, <i>p</i> &lt; 0.001) all-cause mortality. Post-PSM analysis produced consistent findings, with PEG administration linked to reduced 7-day (HR = 0.244, 95% CI 0.168–0.354, <i>p</i> &lt; 0.001) and in-hospital (HR = 0.420, 95% CI 0.337–0.524, <i>p</i> &lt; 0.001) mortality. Subgroup analyses indicated PEG’s protective effect persisted across all clinical subgroups (all <i>p</i>-interaction &gt; 0.005). External validation using Cox regression further confirmed that PEG administration significantly reduced both in-ICU (HR = 0.353, 95% CI 0.211–0.591, <i>p</i> &lt; 0.001) and in-hospital (HR = 0.403, 95% CI 0.268–0.607, <i>p</i> &lt; 0.001) mortality.</p> Conclusion <p>PEG administration improved survival outcomes in critically ill AMI patients, reducing both 7-day and in-hospital all-cause mortality.</p>