Heart failure (HF) and thyroid disease (TD) are 2 common and interacting chronic diseases, and the combined impact of comorbidity on mortality has not been fully studied. This study aims to analyze mortality trends related to HF and TD in the US population from 1999 to 2023 and explore their differences in sex, age groups, race, census region, and urbanization. Based on the CDC WONDER database of the Centers for Disease Control and Prevention, this study extracted death records from adults aged 25 years and older between 1999 and 2023 who listed both HF and TD as the root cause or contributing cause of death. It is encoded using ICD-10 (HF: I50; TD: E00-E07) to identify related cases. Crude mortality and age-adjusted mortality (AAMR) were calculated, and the annual percent change and trend were evaluated by Joinpoint regression analysis. During the study period, a total of 17,37,226 death cases in which HF and TD were both noted on the death certificates were included, and the overall AAMR showed a slight upward trend, from 32.34/1,00,000 in 1999 to 34.19/1,00,000 in 2023. AAMR remained stable from 1999 to 2005, declined significantly from 2005 to 2011, and then continued to rise from 2011. AAMR was higher in men than in women; the crude mortality rate in people aged 85 years and over was significantly higher than in other age groups. Non-Hispanic Blacks have the highest AAMR, followed by non-Hispanic Whites, Hispanics, and other non-Hispanic populations. AAMR is highest in the Midwest, with slightly higher mortality rates in nonmetropolitan areas than in metropolitan areas. The mortality rate associated with HF and TD has been increasing in recent years, and there are significant differences at the levels of sex, age groups, race, census region, and urbanization. There is an urgent need to develop targeted public health strategies to strengthen early prevention, timely diagnosis, treatment adherence, and effective referral to reduce the risk of comorbidity-related mortality and promote systemic medical practice reform.