This study examines social determinants associated with disparities in COVID-19 mortality rates in the United States. Using county-level data, 42 negative binomial mixed models were used to evaluate the impact of social determinants on COVID-19 outcome. First, to identify proper controls, the effect of 24 high-risk factors on COVID-19 mortality rate was quantified. Then, the high-risk terms found to be significant were controlled for in an association study between 41 social determinants and COVID-19 mortality rates. The results describe that ethnic minorities, immigrants, socioeconomic inequalities, and early exposure to COVID-19 are associated with increased COVID-19 mortality, while the prevalence of asthma, suicide, and excessive drinking is associated with decreased mortality. Overall, we recognize that social inequality places disadvantaged groups at risk, which must be addressed through future policies and pro-grams. Additionally, we reveal possible relationships between lung disease, mental health, and COVID-19 that need to be explored on a clinical level.