BACKGROUND AND PURPOSE: Ischemic stroke is a significant public health concern, particularly in Eastern Europe, where the burden remains high. This study aims to evaluate the trends and burden of ischemic stroke in Eastern Europe from 1990 to 2021, providing insights into epidemiological changes and informing public health strategies. METHODS: We used data from the Global Burden of Disease 2021 database to comprehensively assess regional and national ischemic stroke indicators in Eastern Europe. These indicators included the number of cases, incidence, number of deaths, mortality, disability-adjusted life years (DALYs), DALY rates, and estimated annual percentage change (EAPC). Joinpoint analysis was employed to examine sex-specific time trends in the burden of ischemic stroke across Eastern European countries. These estimates incorporated the Socio-Demographic Index (SDI). RESULTS: In 2021, Eastern Europe reported 490,197 cases of ischemic stroke, with an age-standardized incidence rate (ASIR) of 142.57 (95% UI: 122.12 to 164.67), exceeding the global level. The region recorded 329,291 deaths, with an age-standardized mortality rate (ASMR) of 90.99 (95% UI: 82.79 to 98.48), significantly higher than the global rate. Disability-adjusted life years (DALYs) totaled 5,713,718, with an age-standardized DALYs rate (ASDR) of 1601.20 (95% UI: 1483.51 to 1723.12). Our joinpoint regression analysis indicates that the disease burden remains notably high in Eastern Europe, despite an overall declining trend from 1990 to 2021 in ASIR and ASMR across most countries, with estimated annual percentage changes (EAPC) of -1.13 (95% CI: -1.24 to -1.02) and - 2.78 (95% CI: -3.24 to -2.32), respectively. Lithuania reported the highest incidence rate, while the Russian Federation had the highest mortality and DALY rate. Conversely, Estonia showed significant improvements in stroke indicators. Key risk factors included low temperature and smoking, contributing notably to environmental and behavioral risks. CONCLUSION: Ischemic stroke continues to be a significant global health issue. Our temporal trends study results indicate that the disease burden remains notably high in Eastern Europe, particularly in Lithuania and the Russian Federation.