At all levels of socioeconomic status, Black Americans can expect to live shorter and sicker lives than their White counterparts. This study advances the perspective that anti-Black stigma from Whites precludes Blacks from reaping the full health rewards of higher status, particularly within the context of neighborhoods. To test this hypothesis, I merge census data with rich survey and biomarker data from the Nashville Stress and Health Study, a representative sample of Black and White adults from Davidson County, Tennessee (n = 1,252). Initially, I find that Blacks who reside in higher status and mostly White communities exhibit lower levels of neuroendocrine stress hormones, relative to their peers living in disadvantaged Black neighborhoods. But Blacks in higher-status areas also report more perceived discrimination. In turn, perceived discrimination is associated with chronic bodily pain, as well as elevated stress hormones and blood pressure tied to high goal-striving stress, or fears of being blocked from reaching life goals. After accounting for racism-related stressors, Blacks exhibit comparable levels of physiological distress regardless of neighborhood context. The inverse is true for Whites, who report fewer stressors in higher-status neighborhoods, and less physiological distress than Blacks overall. Findings are discussed within the context of social evolutionary theories of the human brain and are dovetailed with broader racial health disparities in the United States.