The poor health of Black men in the United States has been an enigma, hidden in plain sight, for more than 100 years. Although Black men’s poor health is well documented, few research or policy frameworks exist to explain this finding. In this commentary, we use syndemics to explain why Black men in the United States are dying disproportionately from COVID-19 and to guide a framework for efforts to mitigate their risk of dying from COVID-19. Syndemics are defined as 2 or more epidemics interacting synergistically in ways that exacerbate health consequences because of their interaction. The syndemics approach helps to identify how the clustering of structural forces precipitates clustering of disease in specific populations, moving beyond the assumption that these phenomena are separate or coincidental. This framework can be used to guide programmatic and policy initiatives and research priorities to improve Black men’s health and reduce disparities in COVID-19 mortality.