The twenty-first century COVID-19 epidemic revealed a U.S. public health system that countenanced health inequities and a U.S. public that resisted disease containment policies. This crisis, however, was only the most recent chapter in a longer struggle in the United States to institutionalize public health. We focus on two early twentieth-century public health campaigns in the American South, the unhealthiest U.S. region at the time. Black southerners—denied basic health, political, economic, and social rights under a rising Jim Crow regime—self-organized health services networks, including through the Tuskegee Woman’s Club, the Negro Organization Society of Virginia, and the Moveable School (1890s–1915). Around the same time, a philanthropic project, the Rockefeller Sanitary Commission (RSC, 1909–1914), seeded state-level public health agencies in eleven southern states, thereby installing public health in a top-down manner. We use archival data sources to explore key similarities and differences in the public health concerns and coalition-building approaches of each campaign and southern resistance to their efforts. We find Black-led campaigns often blurred the color line to form coalitions that provided services to the underserved while tackling environmental health risks at the community level. In contrast, RSC affiliates in southern states, as directed by RSC administrators, provided health services as short-term public dispensaries. Services reached Black and White communities willing to participate but in a manner that did not overtly challenge Jim Crow-era practices. Southern resistance to public health expansion persisted under each approach. The legacies of these struggles remain; the political-economic and ideological forces that limited public health expansion while marginalizing Black community health efforts reverberate in public health inequities today.