BACKGROUND: Cerebral Atherosclerosis-related mortality remains a major public health issue. This study analyzes trends in age-adjusted mortality rates (AAMR) for cerebral atherosclerosis deaths in the United States from 1999 to 2020. METHODS: Mortality data from 1999 to 2020 for adults aged 25 years and older were analyzed. AAMRs were calculated, and trends were examined for the overall population, as well as by gender, urban-rural areas, race/ethnicity, and census region. Annual percentage changes (APC) were calculated to assess mortality trends. RESULTS: A total of 146 016 deaths were recorded. The overall AAMR increased from 3.44 (95% CI: 3.36-3.53) in 1999 to 7.43 (95% CI: 7.32-7.53) in 2020. Mortality rates initially decreased from 1999 to 2006 (APC: -11.4 [95% CI: -19.7 to -7.85]), followed by a rise, with the sharpest increase from 2013 to 2016 (APC: 36.7 [95% CI: 23.0 to 45.9]). Mortality trends were similar across genders, with both males and females showing increases after an initial decline. Higher AAMRs were seen in urban areas compared to rural regions, with urban areas experiencing a steeper rise post-2013. Racial/ethnic disparities were apparent, with Hispanics showing the largest increase in mortality rates from 1999 to 2020. Regional disparities indicated the highest mortality rates in the South, with a sharp rise from 2012 to 2015. CONCLUSION: Cerebral Atherosclerosis-related mortality rates have significantly increased from 1999 to 2020, with notable disparities across gender, race, and geographic regions. Targeted interventions are needed to address these disparities and reduce mortality, particularly in high-risk populations.