Background: Death from cardiovascular disease (CVD) has been a longstanding public health challenge in the US, whereas death from opioid use is a recent, growing public health crisis. While population-level approaches to reducing CVD risk are known to be effective in preventing CVD deaths, more targeted approaches in high-risk communities are known to work better for reducing risk of opioid overdose. For communities to plan effectively in addressing both public health challenges, they need information on significant community-level (vs individual-level) predictors of death from CVD or opioid use. This study addresses this need by examining the relationship between 1) county-level social determinants of health (SDoH) and CVD deaths and 2) county-level SDoH and opioid-use deaths in the US, over a ten-year period (2009–2018). Methods: A single national county-level ten-year ‘SDoH Database’ is analyzed, to address study objectives. Fixed-effects panel-data regression analysis, including county, year, and state-by-year fixed effects, is used to examine the relationship between 1) SDoH and CVD death-rate and 2) SDoH and opioid-use death-rate. Eighteen independent (SDoH) variables are included, spanning three contexts: socio-economic (e.g., race/ethnicity, income); healthcare (e.g., system-characteristics); and physical-infrastructure (e.g., housing). Results: After adjusting for county, year, and state-by-year fixed effects, the significant county-level positive SDoH predictors for CVD death rate were, median age and percentage of civilian population in armed forces. The only significant negative predictor was percentage of population reporting White race. On the other hand, the four significant negative predictors of opioid use death rate were median age, median household income, percent of population reporting Hispanic ethnicity and percentage of civilian population consisting of veterans. Notably, a dollar increase in median household income, was estimated to decrease sample mean opioid death rate by 0.0015% based on coefficient value, and by 20.05% based on effect size. Conclusions: The study provides several practice and policy implications for addressing SDoH barriers at the county level, including population-based approaches to reduce CVD mortality risk among people in military service, and policy-based interventions to increase household income (e.g., by raising county minimum wage), to reduce mortality risk from opioid overdoses.