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Introduction ‘Deaths of despair’ (DoD)—including suicide, drug overdose and alcohol-related fatalities—have been a growing, 21st century public health issue in the USA. This study quantifies the contributions of age, sex, race/ethnicity and cause or manner of death to changes in the DoD mortality rate. Methods The yearly counts of DoD (1999–2023) for people aged 15 years and older were extracted from CDC Wide-ranging Online Data for Epidemiologic Research. Joinpoint regression was conducted to identify the time point(s) when the change of trend occurred. Decomposition analysis was then conducted for data from 1999 to 2020 to examine the contribution of different subgroups between time points. Results The crude mortality rate of DoD increased from 28.60 per 100 000 population (62 660 deaths) in 1999 to 71.99 (198 266 deaths) in 2023. The joinpoint analysis showed a statistically significant increase from 1999 to 2014 (annual percent change (APC)=2.94%, 95% CI 2.12% to 3.88%) and from 2014 to 2021 (APC=7.27%, 95% CI 2.15% to 11.64%) (average APC (AAPC) 1999–2023=3.96%, 95% CI 3.59% to 4.40%). The decomposition analysis revealed that between 1999 and 2014, persons aged 25–64 contributed 88.72% of the increase, and 98.17% involving non-Hispanic white individuals. Male and drug-related fatalities each contributed about 60% of the increase. While there was no proportional change in the age contributions to increase deaths from 2014 to 2020, only 66.70% of this increase involved non-Hispanic white individuals. During this latter period, male and drug-related fatalities each contributed about 75% of the increase. Conclusion The major contributors to the rise in DoD were deaths among the population aged 25–64, men, non-Hispanic white individuals, and most were drug-related, but the proportion of contributions changed over time.