HIV infection disproportionately affects Blacks in the southern United States (U.S.), a region where legal policies that may unintentionally impede earlier HIV detection and treatment are prevalent. Historically Black Colleges and Universities (HBCUs) have historically facilitated social change in communities of color and have been underexplored as partners for HIV prevention. We describe geographic and social determinants of health (SDH) in the southern U.S. to inform potential HBCU-public health partnerships that might improve HIV health equity. We evaluated the relationship between county-level HIV prevalences (2013), HBCU geographic coordinates, and SDH variables in the southern counties with HBCUs. U.S. Census-derived SDH variables included race/ethnicity (i.e., Black, White, Hispanic), unemployment, female head of household, poverty, percent owner-occupied housing units, urbanicity, and primary care provider rates. Associations were assessed using bivariate and multivariable linear regression. Of 104 HBCUs in the contiguous U.S., 100 (96%) were located in 69 southern counties with average Black populations of 40% and an average HIV prevalence of 615. 5 per 100,000, over two times the national rate (295.1 per 100,000). In bivariable analyses, higher HIV rates in these counties were associated with higher percent Black population, unemployment, female head of household, poverty, fewer owner-occupied housing units, and greater urbanicity (p < 0.05). In multivariable analyses, counties with higher HIV rates had higher percentages of Blacks, greater urbanicity, fewer owner-occupied housing units, and more female heads of households (p < 0.05). The southern U.S. is disproportionately affected by HIV, and many HBCUs are located in affected southern counties. HBCUs may be important public health partners for helping to develop structural interventions that strengthen HIV policies in support of health equity in these southern, mostly urban counties.