BACKGROUND: Asthma remains a public health concern in the United States, with mortality disproportionately affecting demographic groups. This study aimed to describe national trends in asthma mortality from 1999 to 2020 and identify demographic and regional disparities. RESEARCH DESIGN AND METHODS: We retrospectively analyzed mortality data from the CDC WONDER database using International Classification of Diseases, Tenth Revision (ICD-10) codes J45 and J46. Age-adjusted mortality rates (AAMRs) were calculated by sex, race, age group, US Census region, state, and urban-rural classification. Joinpoint regression was employed to detect changes over time. RESULTS: A total of 82,686 asthma-related deaths were identified (37.2% males, 62.8% females). Overall, the AAMR declined from 1.72 in 1999 to 1.14 in 2020. Joinpoint analysis revealed a significant decline from 1999 to 2009, a plateau from 2009 to 2014, a further decline from 2014 to 2018, and a significant increase from 2018 to 2020. Non-Hispanic Black individuals (AAMR 2.73) and older adults (≥65 years) had the highest mortality rates, with females exhibiting higher rates than males (1.30 vs 0.95). CONCLUSIONS: Despite declining trends, persistent disparities in asthma mortality underscore the need for targeted interventions, improved healthcare access, and ongoing surveillance.