Because residents of rural areas in the United States experience a persistent disadvantage in life expectancy relative to their urban counterparts, it is critical to consider the structural and social determinants that affect the health of rural populations. White Americans constitute 3 out of every 4 (76%) rural residents, and there is growing evidence that rurality is a predictor of poor health status for White Americans in ways that are not present for racially minoritized populations or nonrural White populations. We offer a framework to describe Whiteness as a fundamental determinant of the health of rural White Americans, which is useful to more precisely characterize and address the heterogeneous yet unique factors that drive their health. While Whiteness is a dynamic system that typically upholds White Americans’ social supremacy, we provide examples of intermediate (e.g., rural culture, environment) and intrapersonal (e.g., psychosocial) factors through which Whiteness can harm rural White Americans’ health (e.g., chronic disease, mental health). We conclude with a discussion of implications and recommendations that may help to advance research to promote health and well-being among rural White Americans. ( Am J Public Health. Published online ahead of print December 5, 2024:e1–e9. https://doi.org/10.2105/AJPH.2024.307904 )