High COVID-19 mortality among Black communities heightened the pandemic’s devastation. In the state of Louisiana, the racial disparity associated with COVID-19 mortality was significant; Black Americans accounted for 50% of known COVID-19–related deaths while representing only 32% of the state’s population. In this paper, we argue that structural racism resulted in a synergistic framework of cumulatively negative determinants of health that ultimately affected COVID-19 deaths in Louisiana Black communities. We identify the spatial distribution of social, environmental, and economic stressors across Louisiana parishes using hot spot analysis to develop aggregate stressors. Further, we examine the correlation between stressors, cumulative health risks, COVID-19 mortality, and the size of Black populations throughout Louisiana. We hypothesized that parishes with larger Black populations (percentages) would have larger stressor values and higher cumulative health risks as well as increased COVID-19 mortality rates. Our results suggest two categories of parishes. The first group has moderate levels of aggregate stress, high population densities, predominately Black populations, and high COVID-19 mortality. The second group of parishes has high aggregate stress, lower population densities, predominantly Black populations, and initially low COVID-19 mortality that increased over time. Our results suggest that structural racism and inequities led to severe disparities in initial COVID-19 effects among highly populated Black Louisiana communities and that as the virus moved into less densely populated Black communities, similar trends emerged.