Racism is now widely recognized as a fundamental cause of health inequali­ties in the United States. As such, health scholars have rightly turned their attention toward examining the role of struc­tural racism in fostering morbidity and mortality. However, to date, much of the empirical structural racism-health dispari­ties literature limits the operationalization of structural racism to a single domain or orients the construct around a White/ Black racial frame. This operationaliza­tion approach is incomprehensive and overlooks the heterogeneity of historical and lived experiences among other racial and ethnic groups.To address this gap, we present a theoreti­cally grounded framework that illumi­nates core mutually reinforcing domains of structural racism that have stratified opportunities for health in the United States. We catalog instances of structural discrimination that were particularly con­straining (or advantageous) to the health of racial and ethnic groups from the late 1400s to present. We then illustrate the utility of this framework by applying it to American Indians or Alaska Natives and discuss the framework’s broader implica­tions for empirical health research. This framework should help future scholars across disciplines as they identify and interrogate important laws, policies, and norms that have differentially constrained opportunities for health among racial and ethnic groups.Ethn Dis. 2021;31(Suppl 1):301-310; doi:10.18865/ed.31.S1.301