Responding to the call for missionaries to the Congo by the Presbyterian Church in the U.S. (PCUS) General Assembly of 1889, Samuel N. Lapsley, a white man from Alabama, and William H. Sheppard, a black man from Virginia, set sail together in February 1890. They arrived in the Congo in May 1890, and founded the first PCUS mission station at Luebo in 1891. Their attention focused on a number of tribes that spoke the same language, Tshiluba. The two men established Sunday School classes as well as writing and reading classes, and they began to record and learn the native language. In 1897, the arrival of William M. Morrision galvanized the mission, formalizing the language study and increasing evangelistic and social work. The American Presbyterian Congo Mission was able to expand under Belgian rule and during that time, it founded the Morrison Bible School, the John Leighton Wilson Press, a leprosy treatment center, as well as numerous schools. In 1959, the Église Presbytérienne au Congo (Presbyterian Church of the Congo) organized as an independent ecclesiastical body, separate from the control of the mission. Intertribal warfare and disorder after national independence disrupted missionary activity during the early 1960s. Conflict also resulted from the changing nature of the mission and the Presbyterian Church of the Congo. In 1969, the APCM was officially dissolved and mission programs integrated into the work of the Presbyterian Church of the Congo.

Presbyterian work in Mesopotamia dates from 1834 when the American Board of Commissioners for Foreign Missions sent the Reverend and Mrs. Justin Perkins to labor among the Nestorian Christians. The Presbyterian Church in the U.S. began taking control of missions started by the American Board of Commissioners for Foreign Missions in 1870. In 1900 mission work in Iraq was transferred to the English Church Missionary Society (Church of England). In the aftermath of World War I, a united mission was organized and formalized in 1924. Following denominational reorganizations in the 1950s and 1960s, the Reformed Church in America, the PCUS, the United Church of Christ and the UPCUSA constituted the Mission. The Mission was governed through a Joint Committee headquartered in New York. In 1969 the Mission's two schools were nationalized, causing the Joint Committee to suspend indefinitely all of its activities in Iraq. Effective 30 June 1970, the United Mission in Iraq and its governing body were formally dissolved.

The Igreja Evangélica Presbiteriana de Portugal (IEPP) was constituted in 1944, and established the Seminário Evangélico de Teologia at Carcavelos in 1946. Joint mission work in Portugal with the Presbyterian Church of Brazil and the Presbyterian Church in the U.S.A. began the same year. Presbyterian Church in the U.S. mission partnership with the IEPP consisted of support for rural Portuguese Presbyterian congregations, support for youth work camps at the church's conference center, Quinta dos Vais, and sponsorship of students at SET Carcavelos. The PCUS General Assembly Mission Board approved the assignment of an American professor to staff SET Carcavelos in 1975. The assignment was not filled, and PCUS partnership with Portugal effectively ended in 1977.

Oversight of the missions in Iraq, Portugal, and Congo was assigned to the Board of World Missions Area Secretary for Africa, Portugal, and Iraq, Walter D. Shepard, in 1961. The office was renamed the Area Secretary for Africa, Europe, and the Near East in 1962. In 1967, the Board of World Missions was dissolved, and its work was transferred to the General Executive Board, Division of International Mission. In 1982, the office was renamed the Division of International Mission Staff Associate for Africa. Following reunion in 1983, the portfolio for mission partnership in Africa was transferred to the Presbyterian Church (U.S.A.) General Assembly Mission Board Staff Associate for Africa.