Across the U.S., major health inequities persist across several social and structural determinants of health. In this brief, we explored the intersection of these social and structural determinants across major diseases and disease-related mortality. The likelihood of stroke, angina or coronary heart disease, and heart attack (myocardial infarction) was significantly higher in the South and for American Indian or Alaska Native individuals as compared to White individuals. Rural areas of the South experienced high rates of mortality for multiple years related to congestive heart failure, ischemic heart disease, and stroke and cerebrovascular disease. Stroke and cerebrovascular disease mortality were highest in the South as compared to all other regions. Major declines were identified in mortality rates for ischemic heart disease over time (2006-2016). Both region and rurality were critical in assessing mortality with major variation in rates of mortality across each. Major inequities identified in this brief can serve as targets for policymakers in terms of providing additional resources to help reduce the burden of disease facing at-risk populations, particularly rural residents, residents of the South, and American Indians and Alaska Natives.