The Board of Foreign Missions of the Presbyterian Church in the U.S.A. (PCUSA) was organized in 1837 as a result of General Assembly (Old School) action. Its creation marked the culmination of a discussion covering a period of years as to whether missionary operations should be carried on by voluntary societies, or by the Church in its organized capacity. Like its immediate predecessor, the Western Foreign Missionary Society, the Board's purpose was to convey the Gospel "to whatever parts of the heathen and anti Christian world, the Providence of God might enable the Society to extend its evangelical exertions." From 1837 until 1862, the Board was a benevolent society of the Presbyterian Church, with no legal status. In 1862 the Board was incorporated by the state of New York.

Throughout the l9th and 20th centuries the Board directed the foreign and domestic missionary activities of the PCUSA. Under the Board's administration missions were established in Mexico, Central and South America, Africa, Syria, Persia, India, Siam, Laos, China, Japan, Korea, and the United States (to the Native American, Jewish, Chinese and Japanese populations). Missions to the Native American and Jewish populations were transferred to the Board of Home Missions in 1893 and 1894 respectively. Asian-American mission work was transferred to the Board of Home Missions in 1922.

The Board remained in existence until 1958 at which time its work was transferred to the Commission on Ecumenical Mission and Relations of the newly formed UPCUSA. In 1972, as a result of reorganization within the Church, the foreign mission activities were placed under the direction of the Program Agency.