Aim <p>To analyze the trends in deaths of despair (DOD) in Mexico between 1990 and 2021 using data from the Global Burden of Disease (GBD) Study 2021 by sex and state, and to assess their association with the Socio-Demographic Index and the Healthcare Access and Quality Index.</p> Subject and methods <p>Secondary data analysis was conducted using the GBD-2021 study. The paper analyzes mortality, premature mortality, disability, and disability-adjusted life years (DALYs). A log-linear segmented regression model to analyze trends in DOD DALY rates over time was used. The information was disaggregated by age subgroups and sub-causes, both at the national level and for the 32 states.</p> Results <p>DOD mortality in Mexico has decreased since 1990, but with significant increases in deaths from drug-use-disorder and self-harm. The DALY rates were notably higher for men, who experienced a 5.4 times higher rate than women. Cirrhosis due to alcohol and self-harm represented the largest share of the DOD burden. Alcohol-related diseases decreased for both sexes, while self-harm presented an increasing trend from 1990 through 2021. Male adults and younger female individuals were most affected by DOD. Regionally, Chihuahua and Yucatán had the highest male DOD burden in 2021, while Morelos and Sinaloa reported the lowest rates. Increased levels of SDI and HAQI were strongly associated with lower DOD burden.</p> Conclusion <p>This study provides a comprehensive analysis of DOD within Mexico and offers valuable insights and a foundation for further research to inform policies and interventions aimed at reducing the preventable burden of DOD.</p>