The United States has the highest number of coronavirus disease 2019 (COVID-19) in the world, with high variability in cases and mortality between communities. We aimed to quantify the associations between socio-economic status and COVID-19–related cases and mortality in the U.S. The study design includes nationwide COVID-19 data at the county level that were paired with the Distressed Communities Index (DCI) and its component metrics of socio-economic status. Severely distressed communities were classified by DCI>75 for univariate analyses. Adjusted rate ratios were calculated for cases and fatalities per 100,000 persons using hierarchical linear mixed models. This cohort included 1,089,999 cases and 62,298 deaths in 3127 counties for a case fatality rate of 5.7%. Severely distressed counties had significantly fewer deaths from COVID-19 but higher number of deaths per 100,000 persons. In risk-adjusted analysis, the two socio-economic determinants of health with the strongest association with both higher cases per 100,000 persons and higher fatalities per 100,000 persons were the percentage of adults without a high school degree (cases: RR 1.10; fatalities: RR 1.08) and proportion of black residents (cases and fatalities: Relative risk(RR) 1.03). The percentage of the population aged older than 65 years was also highly predictive for fatalities per 100,000 persons (RR 1.07). Lower education levels and greater percentages of black residents are strongly associated with higher rates of both COVID-19 cases and fatalities. Socio-economic factors should be considered when implementing public health interventions to ameliorate the disparities in the impact of COVID-19 on distressed communities. •Socio-economic factors play an important role in coronavirus disease 2019 (COVID-19) prevalence and mortality.•Lower education level was the strongest association with both cases and fatalities.•The higher proportion of Black residents was also associated with cases and fatalities.•The poverty rate and median income were also associated with COVID-19 cases.•Median income and change in employment were also associated with COVID-19 fatalities.