Background: Ischemic stroke remains a major cause of disability worldwide, especially impacting the middle-aged workforce (40–64 years). This study examines the global burden of ischemic stroke within this age group from 1990 to 2021, focusing on the attributable risk factors stratified by age, sex, and sociodemographic index (SDI). Methods: Utilizing data from the Global Burden of Disease (GBD) Study 2021 across 204 countries, the study employed the DisMod-MR 2.1 Bayesian meta-regression model to estimate the incidence, mortality, and disability-adjusted life years (DALYs) related to ischemic stroke. Data were analyzed by age, sex, and SDI categories to reveal variations over time and across regions. The study also assessed 88 risk factors, calculating population attributable fractions for DALYs. Results: In 2021, the global age-standardized incidence, DALY, and mortality rates for ischemic stroke among the middle-aged workforce were 107.5, 736.9, and 17.1 per 100,000, respectively. High-middle SDI countries exhibited the highest incidence and DALY rates, whereas low-middle SDI countries had the highest mortality rate. High SDI countries reported the lowest rates overall. Men, particularly aged 55–64, faced higher rates compared to women. Eastern Europe recorded the highest regional rates, with Turkmenistan showing the highest incidence and DALY rates, and Afghanistan the highest mortality rate. The primary risk factors contributing to DALYs were high systolic blood pressure, high LDL cholesterol, and smoking. In low SDI regions, household air pollution also played a significant role. Conclusion: Despite overall reductions in stroke burden, ischemic stroke remains a significant public health issue, especially in men and high-middle SDI regions. Effective control of major risk factors like high blood pressure, high LDL cholesterol, and smoking is crucial. Customized prevention programs based on regional and economic contexts are essential to address this persistent health challenge.

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