Racial and ethnic disparities in healthcare and health outcomes are longstanding. The real-time emergence of COVID-19 disparities has heightened the public and scientific discourse about structural inequities contributing to the greater risk of morbidity and mortality among racial and ethnic minority populations and other underserved groups. A key aspect of assuring health equity is addressing social determinants that lead to adverse health outcomes among minoritized groups. This article presents an exploratory social determinants of health (SDOH) conceptual framework for understanding racial and ethnic COVID-19 disparities, including factors related to health and healthcare, socioeconomics, and environmental determinants. The model also illustrates the backdrop of structural racism and discrimination, which directly affect health and COVID-19 exposure risk, and thus transmission, infection, and death. We also describe a special SDOH collection in the PhenX Toolkit (consensus measures for Phenotypes and eXposures), which includes established measures to promote standardization of assessment and the use of common data elements in research contexts. The use of common constructs, measures, and data elements are important for data integration, understanding the causes of health disparities, and evaluating interventions to reduce them. Substandard SDOH are among the primary drivers of health disparities-and scientific approaches to address these key concerns require identification and leveled alignment with the root causes. The overarching goal of this discussion is to broaden the consideration of mechanisms by which populations with health disparities face additional SARS-CoV-2 exposure risks, and to encourage research to develop interventions to reduce SDOH-associated disparities in COVID-19 and other conditions and behaviors.