This global analysis shed light on health disparities by sex in deaths of despair, especially concerning trends in the US. It identified countries and groups in need of targeted mental health and substance-use programs. Moreover, the disparities by sex revealed in this analysis suggest that mental health and substance-use interventions and programs may need to be more attentive to sex and/or gender, such as inequitable social norms and restrictive forms of masculinities, which have been shown to be contributing factors to deaths of despair.