<p>Little is known about how acute myocardial infarction (AMI) mortality has changed over the past two decades in young US adults. We aimed to evaluate the AMI mortality trend among young adults in the US from 1999 to 2020. Data were extracted from the US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database. Young adults aged 15–44 years with AMI listed as a contributing or underlying cause of death were included. Joinpoint regression was used to estimate the annual percent changes (APCs) and average annual percentage changes (AAPCs) in AMI-related age-adjusted mortality rates (AAMRs). There were 81,272 AMI-related deaths among young adults. The overall AAMR shows a stable trend from 1999 to 2003 (APC 0.2%); a steeper decrease from 2003 to 2009 (APC -4.2%); a steady decrease from 2009 to 2018 (APC -1.8%); and a significant increase from 2018 to 2020 (APC 7.3%); with an AAPC of -1.3% per year (95% CI -2.0% to -0.5%). The AAMR significantly decreased among men (AAPC -1.5%; 95% CI -2.2% to -0.7%), women (AAPC -1.0%; 95% CI -2.4% to -0.4%), non-Hispanic White (AAPC -1.9%; 95% CI -2.6% to -1.1%), and non-Hispanic or African American (AAPC -1.2%; 95% CI -1.8% to -0.6%). Across all geographical regions, the AAMR declined, most significantly in large metropolitan areas (AAPC -1.8%; 95% CI -2.7% to -0.8%). In conclusion, AMI mortality rates among young adults mostly declined from 1999 to 2020, with significant demographic and geographic variation.</p>