Background Residential segregation, a geospatial manifestation of structural racism, is a fundamental driver of racial and ethnic health inequities, and longitudinal studies examining segregation's influence on cardiovascular health are limited. This study investigates the impact of segregation on hypertension in a multiracial and multiethnic cohort and explores whether neighborhood environment modifies this association. Methods and Results Leveraging data from a diverse cohort of adults recruited from 6 sites in the United States with 2 decades of follow-up, we used race- and ethnicity-stratified Cox models to examine the association between time-varying segregation with incident hypertension in 1937 adults free of hypertension at baseline. Participants were categorized as residing in segregated and nonsegregated neighborhoods using a spatial-weighted measure. We used a robust covariance matrix estimator to account for clustering within neighborhoods and assessed effect measure modification by neighborhood social or physical environment. Over an average follow-up of 7.35 years, 65.5% non-Hispanic Black, 48.1% Chinese, and 53.7% Hispanic participants developed hypertension. Net of confounders, Black and Hispanic residents in segregated neighborhoods were more likely to develop hypertension relative to residents in nonsegregated neighborhoods (Black residents: hazard ratio [HR], 1.33; 95% CI, 1.09-1.62; Hispanic residents: HR, 1.33; 95% CI, 1.04-1.70). Results were similar but not significant among Chinese residents (HR, 1.20; 95% CI, 0.83-1.73). Among Black residents, neighborhood social environment significantly modified this association such that better social environment was associated with less pronounced impact of segregation on hypertension. Conclusions This study underscores the importance of continued investigations of groups affected by the health consequences of racial residential segregation while taking contextual neighborhood factors, such as social environment, into account.