Given the challenges related to reducing socio-economic and health inequalities, building specific health system approaches for Indigenous peoples is critical. In Brazil, following constitutional reforms that led to the universalization of health care in the late 1980s, a specific health subsystem was created for Indigenous peoples in 1999. In this paper, we use a historical perspective to contextualize the creation of the Indigenous Health Subsystem in Brazil. This study is based on data from interviews with Indigenous and non-Indigenous subjects and document-based analysis. In the 1980s, during the post-dictatorship period in Brazil, the emergence of Indigenous movements in the country and the support for pro-Indigenous organizations helped establish a political agenda that emphasized a broad range of issues, including the right to a specific health policy. Indigenous leaders established alliances with participants of the Brazilian health reform movement, which resulted in broad debates about the specificities of Indigenous peoples, and the need for a specific health subsystem. We highlight three main points in our analysis: (1) the centrality of a holistic health perspective; (2) the emphasis on social participation; (3) the need for the reorganization of health care. These points proved to be convergent with the development of the Brazilian health reform and were expressed in documents of the Indigenist Missionary Council (CIMI) and the Union of Indigenous Nations (UNI). They were also consolidated in the final report of the First National Conference on the Protection of Indigenous Health in 1986, becoming the cornerstone of the national Indigenous health policy declared in 1999. Our analysis reveals that Indigenous people and pro-Indigenous groups were key players in the development of the Indigenous Health Subsystem in Brazil.