This study examines how social determinants associated with COVID-19 mortality change over time. Using US county-level data from July 5 and December 28, 2020, the effect of 19 high-risk factors on COVID-19 mortality rate was quantified at each time point with negative binomial mixed models. Then, these high-risk factors were used as controls in two association studies between 40 social determinants and COVID-19 mortality rates using data from the same time points. The results indicate that counties with certain ethnic minorities and age groups, immigrants, prevalence of diseases like pediatric asthma and diabetes and cardiovascular disease, socioeconomic inequalities, and higher social association are associated with increased COVID-19 mortality rates.