<p>The Hemoglobin Glycation Index (HGI) quantifies the discrepancy between observed and predicted glycated hemoglobin (HbA1c) levels, reflecting individual variations in glycation. Elevated HGI has been associated with adverse outcomes in various populations, but its prognostic significance in acute ischemic stroke (AIS) patients remains unclear. We conducted a retrospective cohort study using the MIMIC-IV 2.2 database, including 8,368 first-time ICU admissions diagnosed with AIS. 2,642 patients underwent HbA1c testing. Patients were stratified into tertiles: Q1 (HGI &lt; − 0.56), Q2 (− 0.56 ≤ HGI ≤ 0.01), and Q3 (HGI &gt; 0.01). Baseline characteristics, comorbidities, and clinical variables were compared across groups. Cox proportional hazards models assessed the association between HGI levels and all-cause mortality at 28 and 365 days. Subgroup analyses were performed to explore interactions with key variables. Restricted Cubic Spline (RCS) analysis was utilized to assess the nonlinear relationship between continuous HGI values and mortality risk. The cohort comprised 886 (Q1), 876 (Q2), and 880 (Q3) patients. Kaplan-Meier analysis showed that Q2 exhibited significantly higher 28-day and 365-day survival rates compared to Q1 and Q3 groups (<i>P</i> &lt; 0.001). Cox models indicated that both Q1 and Q3 had elevated mortality risks compared to Q2 at 28 and 365 days. RCS plots revealed a nonlinear, U-shaped association between continuous HGI values and mortality risk at both 28 and 365 days. HGI is a significant prognostic factor in AIS patients, with both low and high HGI levels associated with increased mortality risk. These findings underscore the potential of HGI as a tool for risk stratification in AIS.</p>