Racial residential segregation has been associated with an increased risk for heart disease and stroke deaths. However, there has been little research into the role that candidate mediating pathways may play in the relationship between segregation and heart disease or stroke deaths. In this study, we examined the relationship between metropolitan statistical area (MSA)-level segregation and heart disease and stroke mortality rates, by age and race, and also estimated the effects of various educational, economic, social, and health-care indicators (which we refer to as pathways) on this relationship. We used Poisson mixed models to assess the relationship between the isolation index in 265 U.S. MSAs and county-level (heart disease, stroke) mortality rates. All models were stratified by race (non-Hispanic black, non-Hispanic white), age group (35–64 years, ≥65 years), and cause of death (heart disease, stroke). We included each potential pathway in the model separately to evaluate its effect on the segregation–mortality association. Among blacks, segregation was positively associated with heart disease mortality rates in both age groups but only with stroke mortality rates in the older age group. Among whites, segregation was marginally associated with heart disease mortality rates in the younger age group and was positively associated with heart disease mortality rates in the older age group. Three of the potential pathways we explored attenuated relationships between segregation and mortality rates among both blacks and whites: percentage of female-headed households, percentage of residents living in poverty, and median household income. Because the percentage of female-headed households can be seen as a proxy for the extent of social disorganization, our finding that it has the greatest attenuating effect on the relationship between racial segregation and heart disease and stroke mortality rates suggests that social disorganization may play a strong role in the elevated rates of heart disease and stroke found in racially segregated metropolitan areas.