Background: The incidence of premature myocardial infarction (PMI) in women (<65 years and men <55 years) is increasing. We investigated proportionate mortality trends in PMI stratified by sex, race, and ethnicity. Methods and Results: CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research) was queried to identify PMI deaths within the United States between 1999 and 2020, and trends in proportionate mortality of PMI were calculated using the Joinpoint regression analysis. We identified 3 017 826 acute myocardial infarction deaths, with 373 317 PMI deaths corresponding to proportionate mortality of 12.5% (men 12%, women 14%). On trend analysis, proportionate mortality of PMI increased from 10.5% in 1999 to 13.2% in 2020 (average annual percent change of 1.0 [0.8-1.2, P <0.01]) with a significant increase in women from 10% in 1999 to 17% in 2020 (average annual percent change of 2.4 [1.8-3.0, P <0.01]) and no significant change in men, 11% in 1999 to 10% in 2020 (average annual percent change of -0.2 [-0.7 to 0.3, P=0.4]). There was a significant increase in proportionate mortality in both Black and White populations, with no difference among American Indian/Alaska Native, Asian/Pacific Islander, or Hispanic people. American Indian/Alaska Natives had the highest PMI mortality with no significant change over time. Conclusions: Over the last 2 decades, there has been a significant increase in the proportionate mortality of PMI in women and the Black population, with persistently high PMI in American Indian/Alaska Natives, despite an overall downtrend in acute myocardial infarction-related mortality. Further research to determine the underlying cause of these differences in PMI mortality is required to improve the outcomes after acute myocardial infarction in these populations.