Introduction: The purpose of this study is to examine nationwide disparities in drug, alcohol, and suicide mortality; evaluate the association between county-level characteristics and these mortality rates; and illustrate spatial patterns of mortality risk to identify areas with elevated risk.Methods: The authors applied a Bayesian spatial regression technique to investigate the associa-tion between U.S. county-level characteristics and drug, alcohol, and suicide mortality rates for 2004-2016, accounting for spatial correlation that occurs among counties. Results: Mortality risks from drug, alcohol, and suicide were positively associated with the degree of rurality, the proportion of vacant housing units, the population with a disability, the unemployed population, the population with low access to grocery stores, and the population with no health insurance. Conversely, risks were negatively associated with Hispanic population, non-Hispanic Black population, and population with a bachelor's degree or higher.Conclusions: Spatial disparities in drug, alcohol, and suicide mortality exist at the county level across the U.S. social determinants of health; educational attainment, degree of rurality, ethnicity, disability, unemployment, and health insurance status are important factors associated with these mortality rates. A comprehensive strategy that includes downstream interventions providing equi-table access to healthcare services and upstream efforts in addressing socioeconomic conditions is warranted to effectively reduce these mortality burdens. Am J Prev Med 2023;64(2):149-156.(c) 2022 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.