A National Institute of Neurological Disorders and Stroke working group developed the Determinants of Inequities in Neurological Disease, Health, and Well-being framework. Our goal was to guide and inspire a new generation of neurologic research that pushes the field to design and test new approaches in pursuit of health equity, population health, and social justice. We seek to expand the lens of those looking to reduce or eliminate racial, socioeconomic status, and other inequities in neurologic disease, health, and well-being to improve our collective ability to create research, programs, and policies that lead to larger, more impactful, and more sustainable change in neurologic disease patterns. In this context, we outline a framework that includes and highlights “upstream” factors in the hopes of enhancing the focus of research, programmatic, and policy efforts to reduce and eliminate inequities in neurologic health and well-being. We explicitly discuss racism and other structural factors to clarify that social determinants are not natural and unchangeable. Populations with a disproportionate burden of neurologic disease are not inherently deficient, despite what some approaches to framing health inequities imply. The framework is presented linearly, but the pathways linking the determinants of neurologic disease, health, and well-being are far more complex than those demonstrated by the arrows included in the figure. The framework highlights the different levels and scale of causation, including the structural and intermediary social determinants and their impact on neurologic health. We offer this framework to refine efforts to contextualize the interpretation of neurologic research findings and suggest new avenues for their application. We illustrate how behavioral and biological factors occur in a social and economic context, factors that have been understudied as points of intervention to reduce inequities in neurologic disease. Considering social and structural determinants of health provides promising new opportunities to achieve neurologic health equity, reach social justice, and improve our science. Extending our work in this fashion is not simply about health equity or social justice but to fundamentally improve the quality of neurologic research by enhancing underlying theory and improving study design and implementation.