Background <p>Heart Failure (HF) and Pulmonary Embolism (PE)-related mortality rates are increasing annually in the United States. Disparities in cardiovascular outcomes are well established across ethnicity, sex and geography. The study aims to analyze the mortality trends in HF and PE-related mortality and the disparities in sex, race and geagraphy in the US (1999–2020).</p> Methods <p>The study analyzed HF and PE-related mortality rates using death certificate data from the CDC WONDER database under Multiple Causes of Death (MCOD) file. Age-Adjusted Mortality Rates (AAMR) per 100,000 population, Annual Percent Changes (APCs) and Confidence Intervals (CIs) were calculated. Data were further stratified by year, sex, race, and geographic region.</p> Results <p>This study examined 60,072 deaths related to HF and PE among U.S. adults aged 25–85 + years. The AAMR increased from 1.1 (95% CI: 1.05–1.15) to 1.88 (95% CI: 1.83–1.93), with a sharp rise from 2018 to 2020 (APC = 12.14). The total number of deaths increased from 1,980 to 5,026. Mortality was higher among females (56.07%) than males (43.93%), and men exhibited higher AAMRs (1.35) than females (1.2), AAMRs among men increased from 1.25 to 2.14 (2013–2020, APC = 7.21), AAMRs among females increased from 1.3 to 1.66 (2018–2020, APC = 12.16). Racial disparities were evident, with non-Hispanic (NH) Black individuals having the highest AAMR (2.10), followed by NH Whites (AAMR = 1.24), NH American Indian or Alaska Natives (AAMR = 1.13) and Hispanics (AAMR = 0.41) Geographic differences were notable, with the Midwest Region having the highest AAMR 4 (1.38–1.42). Wyoming recorded the highest AAMR (2.05), while Hawaii had the lowest (0.65). States Texas (AAMR = 1.55) and California (AAMR = 1.12) contributed the highest total deaths.</p> Conclusion <p>HF and PE-related AAMR increased in the US from 1999 to 2020. AAMRs were seen more in men, NH black Africans, and southern regions.</p>