While the National Institutes of Health emphasize integrating sex as a biological variable into research, specific considerations of sex-related differences in pulmonary embolism (PE) mortality trends remain scarce. This study examines sex-based PE mortality trends across regional and demographic groups in the USA from 1999 to 2020. A retrospective analysis of National Center for Health Statistics mortality data from 1999 to 2020 was conducted. Using ICD-10 code I26, PE decedents were identified. Piecewise linear regression assessed sex-based temporal trends in PE mortality by age, race/ethnicity, and census region. Annual percentage changes and average annual percentage changes were derived using Weighted Bayesian Information Criteria. The 95% confidence intervals were estimated using the empirical quantile method. From 1999 to 2020, a total of 179,273 individuals died in the USA due to PE, resulting in an age-adjusted mortality rate of 2.5 per 100,000 persons (95% CI, 2.5-2.5). While men and women exhibited comparable rates in recent time segments and across most subcategories, a higher mortality trend among males compared to females was observed among non-Hispanic White and Hispanic individuals and residents of the Western US census region. These results remained robust even after excluding data from 2020, accounting for the potential impact of the COVID-19 pandemic. Our study highlights sex-based disparities in PE mortality trends in the USA from 1999 to 2020. Despite overall stable mortality rates, higher trends among males were evident in specific demographic groups and regions. These findings emphasize the importance of targeted interventions to mitigate PE-related mortality discrepancies across diverse populations.