The history of the Southeastern United States is characterized by a complex interplay of Indigenous presence and European colonization. Indigenous populations inhabited the region for centuries prior to the arrival of French, English, and Spanish settlers in the seventeenth century, whose incursions precipitated the displacement of Indigenous groups from their ancestral lands. Throughout the eighteenth century, colonial settlers advanced entrepreneurial initiatives while increasingly relying on the labor of Indigenous peoples, women, children, and African Americans to facilitate the nation’s independence and westward expansion. This period was defined by ideological commitments to self-reliance, the principle of “free suffrage,” and the elevation of the “common man,” which collectively contested the prevailing notion that property ownership was essential for men to contribute to the nation’s economic development. Notwithstanding the formal abolition of slavery following the American Civil War (1861–1865), systems analogous to indentured servitude persisted in various parts of the Southeast. Following the Women’s Suffrage Movement (1848–1920) and the Civil Rights Movement (1954–1968), minority groups increasingly attained greater socio-economic, political, and legal equality. This chapter explores the intersection of social and racial factors and their implications for health outcomes within the region.