Acute myocardial infarction (AMI)–related mortality has been decreasing within the United States because of improvements in management and preventive efforts; however, persistent disparities in demographic subsets such as race may exist. In this study, the nationwide trends in mortality related to AMI in adults in the United States from 1999 to 2019 are described. Trends in mortality related to AMI were assessed through a cross-sectional analysis of the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database. Age-adjusted mortality rates per 100,000 people and associated annual percentage change and average annual percentage changes with 95% confidence intervals (CIs) were determined. Joinpoint regression was used to assess the trends in the overall, demographic (gender, race/ethnicity, age), and regional groups. Between 1999 and 2019, a total of 3,655,274 deaths related to AMI occurred. In the overall population, age-adjusted mortality rates decreased from 134.7 (95% CI 134.2 to 135.3) in 1999 to 48.5 (95% CI 48.3 to 48.8) in 2019 with an average annual percentage change of −5.0 (95% CI −5.5 to −4.6). Higher mortality rates were seen in Black individuals, men, and those living in the South. Patients older than 85 years experienced substantial decreases in mortality. In addition, rural counties had persistently higher mortality rates in comparison with urban counties. In conclusion, despite decreasing mortality rates in all groups, persistent disparities continued to exist throughout the study period.