OBJECTIVE: Around 7.7% of Americans have asthma, including 20.2 million adults and 4.6 million children. This study examines asthma mortality trends and disparities across U.S. demographic and geographic groups from 1999 to 2020. METHODS: A retrospective analysis was conducted using the CDC WONDER database to examine asthma-related deaths in the U.S. from 1999 to 2020. Age-adjusted mortality rates (AAMRs) and crude mortality rates (CMRs) per 100,000 were calculated. Trends and annual percent changes (APCs) were assessed overall and stratified by sex, race, region, and age. RESULTS: From 1999 to 2020, the U.S. recorded 221 161 asthma-related deaths (AAMR: 3.07), mostly in medical facilities. Mortality declined from 1999 to 2018 (APC: -1.53%) but surged from 2018 to 2020 (APC: 28.63%). Females, NH Blacks, and NH American Indians had the highest mortality rates. Older adults (≥65) had the greatest burden, with younger groups showing notable increases post-2018. Rural areas and the West reported slightly higher rates than urban and other regions. Hawaii and the District of Columbia had the highest AAMRs, while Florida and Nevada had the lowest. CONCLUSION: Asthma-related mortality in the U.S. declined until 2018 but sharply increased from 2018 to 2020, with rises across all demographic groups, regions, and settings. Females, NH Blacks, and older adults consistently had higher mortality rates, while younger age groups showed recent alarming increases. Targeted interventions are urgently needed to address inequities and recent mortality surges.