The first North American Presbyterian missionary to Brazil was Rev. Ashbel Green Simonton, who was sent to Rio de Janeiro in 1859 by the Board of Foreign Missions of the Presbyterian Church in the U.S.A. (PCUSA). Ten years later, the Executive Committee of Foreign Missions of the recently formed Presbyterian Church in the U.S. (PCUS) sent Rev. and Mrs. George Nash Morton and Edward Lane to Campinas, in the state of São Paolo, to establish the Brazil Mission of the Southern stream of the Presbyterian Church. When they arrived, the first presbytery of the Presbyterian Church of Brazil (Igreja Presbiteriana do Brasil, or IPB), the Presbytery of Rio de Janeiro, had been in place for several years. The first synod was formed in 1888, with 52 churches in four presbyteries.

Unlike other Presbyterian foreign fields, mission work in Brazil was not structured around permanent centralized stations; instead, much of the work was done by itinerant evangelistic missionaries, who planted churches, and educational missionaries who opened primary schools for new church members, and established colleges, industrial schools, and theological seminaries. The PCUS Brazil Mission engaged in a number of specialized ministries, including agricultural and resettlement projects; missions to Korean immigrants and to indigenous groups; literature production and distribution; and literacy programs, such as the ABC Crusade (Cruzada de Ação Básica Cristã), launched in 1965 by the North Brazil Mission. The mission was a member of the multidenominational Evangelical Confederation of Brazil (Confederação Evangélica do Brasil) and participated in cooperative projects such as the Protestant Audio-Visual Center (Centro Audio-Visual Evangélico, or CAVE ); the Caiuá Indian Mission and Bible Institute; adult education programs; and large-scale evangelistic campaigns. Because of legal restrictions on foreign medical work, the missionaries of the PCUS Brazil Mission did not carry out as much hospital building as in other foreign fields, but the mission supported local medical workers, and a number of missionaries, including Dr. George Butler, obtained Brazilian medical licenses.

For the first several years, the work of the PCUS Brazil Mission was concentrated around Campinas in the south, but by the early 1880s, stations had been opened in the northern cities of Recife, Fortaleza, and São Luiz. Managing such a vast mission field was a challenge; in 1884, the North Brazil Mission was established as a separate administrative entity. The mission’s acquisition of airplanes beginning in the 1950s greatly facilitated work in remote regions. The North Brazil Mission eventually encompassed stations in the states of Pará, Maranhão, Piauí, Ceará, Rio Grande do Norte, Paraiba, Pernambuco, Alagoas, and Northern Goiás. Schools founded by the mission include the Fifteenth of November School in Garanhuns; the Agnes Erskine School in Recife; the Presbyterian Theological Seminary of the North in Garanhuns/Recife; and the Bible Institute of the North in Garanhuns.

In 1906, the Southern Brazil Mission (not to be confused with the PCUSA’s South Brazil Mission) was reorganized into the East and West Brazil Missions. The East Brazil Mission included stations in the southern states of São Paolo, Minas Gerais, Southern Mato Grosso, Southern Goiás, and Guanabara. Much of the work of the East Brazil Mission involved the educational complex at Lavras, which included the Gammon Institute, an agricultural school, and the Charlotte Kemper Seminary. Missionaries of the East Brazil Mission also founded the Harriet Armstrong Evangelical School in Campo Belo; the Allyn Protestant School in Varginha, and the Erasmo Braga School in Dourados. In 1946, the mission established a Language and Orientation School for missionaries in Uberlândia, Minas Gerais.

The West Brazil Mission comprised a small contingent of missionaries who organized churches in the states of Goiás, Southern Minas Gerais, and Northern São Paolo. The missionaries of the West Brazil Mission established primary schools, the Edward Lane Bible Institute in Patrocínio, and the Campinas Seminary. In the mid 1950s, the West Brazil mission opened the Bandeirante School in Ceres, Goiás, a boarding school for the children of missionaries and other Americans living in Brazil.

In 1967, the three mission regions merged to become the Brazil Presbyterian Mission, divided for administrative purposes into four regions.

The mission boards of the PCUS and the PCUSA encouraged the early establishment and transfer of mission work to the IPB. By the turn of the twentieth century, a growing divergence of opinion on matters of doctrine, policy and methods resulted in a schism in the national church. In 1903, a number of ministers, elders and communicants, led by Rev. Eduardo Carlos Pereira, withdrew from the Presbyterian Church of Brazil and established the Independent Presbyterian Church of Brazil, which did not maintain any connection to the American missions.

The PCUS and PCUSA missions continued to work with the IPB. In 1917, the General Assembly of the IPB adopted the Modus Operandi Plan, also called the Brazil Plan, under which the American missionaries agreed to withdraw from the presbyteries, and to focus largely on evangelism and education. The national church and the American missions worked in parallel, but also in isolation from each other, until a Modus Operandi Commission was formed in the early 1940s to work towards greater cooperation. In 1954, the IPB and the PCUS and PCUSA Brazil Missions formed the Inter-Presbyterian Council (Conselho Inter-Presbiteriano) to coordinate all Presbyterian work and to plan for the eventual integration of the missions and the national church, including the transfer of churches established by the mission to the management of the national church.

In 1971, the Central Brazil Mission of the UPCUSA was dissolved and replaced with a missionary advisory committee; shortly afterward, the IPB terminated its relationship with the UPCUSA mission, bringing to a conclusion a long history of tension between the two bodies. In 1973, the PCUS Brazil Mission and the IPB formed the Permanent Commission on Presbyterian Cooperation (Comissão Permanente de Cooperação Presbiteriana) to manage the accelerating transfer of mission institutions and evangelical work to the national church. The PCUS Brazil Mission was formally dissolved in 1985.