Presbyterians were the first Protestants to initiate missionary work in Mexico. Though the Board of Foreign Missions formally commenced work in 1872, it had in fact begun the task thirtythree years earlier, sending the Reverend and Mrs. William C. Blair and the Reverend Daniel Baker to the newly independent republic of Texas in a move designed to be a stepping stone to mission work south of the Rio Grande.

Until 1857, all forms of religion except Roman Catholicism were forbidden in Mexico. In that year, liberal leader Benito Juarez passed legislation permitting freedom of worship, thus encouraging the development of evangelical churches. In 1866, Melinda Rankin opened a school in Monterrey which was later transferred to Saltillo. Stirrings of independent thought manifested themselves in many of the northern towns and in Mexico City, resulting in the establishment of study groups under the direction of Arcadio Morales, T.F. Wallace, Maxwell Phillips, the Reverend C.C. Millar and Dr. J.M. Greene. In 1872, the General Assembly voted to establish a formal mission in Mexico, building upon the work of these earlier leaders. The Board appointed the Reverend and Mrs. Henry C. Thomson, the Reverend and Mrs. Maxwell Phillips, the Reverend Paul Henry Pitkin, the Reverend and Mrs. Merrill N. Hutchinson and Miss Ellen P. Allen as its first missionaries.

The Mexico Mission, like others throughout Latin America, operated on a decentralized basis. Administratively, only two stations existed: Central Station, founded in 1872, and Peninsula Station, founded in 1915. The former included Vera Cruz (1897) and Oaxaca (1919): the latter included the three states of Yucatan, Campeche, Tabasco and the territory of Quintano Roo. In 1915, a plan was devised among the various denominations operating in Mexico to address the uneven distribution of Protestant missionaries throughout Mexico. As a result of the "Cincinnati Plan," the Presbyterian Church surrendered its older established work in the States of Zacatecas, Guerrero and Michoacan and limited itself to the areas previously described.

Despite its legal status, Protestant mission work in Mexico was subject to both religious and political persecution. Tension between the Mexican and American governments thwarted the work of the Church. Strife among various Mexican political factions and the subsequent turmoil of civil war and revolution further retarded the work of the Church. The Mexican Constitution of 1917 and the enactment of legislation during the 1930s limited Protestant influence in such areas as ordination of ministers, education and the ownership of property. Though private worship was not to be interfered with, public worship was only to be held in church buildings specifically recognized by the State. Anticlericalism and fear of religious organizations in general formed the basis of these restrictions.

Despite these restrictions, the PCUSA ministered to the educational and evangelistic needs of the Mexican people. Though the mission did not engage in any regular medical work, it did conduct modest clinic work and it shared in the training of nurses in the Baptist Hospital in Puebla and in the Southern Presbyterian Hospital in Morelia. Schools were established in San Angel (later called Villa Obregon), Coyoacan and in the State of Oaxaca. Bible Training Schools also flourished in the Federal District, in Oaxaca and in Merida, Yucatan where the Turner-Hodge School for girls and boys attracted large numbers of students. Since the 1930s, the concept of Christian education has been increasingly difficult to implement given the rise of state-supported secular schools and the constitutional restrictions on religious instruction. Formal evangelical work, though also limited, was conducted among the military and the students. Small congregations, initially lead by missionaries of the PCUSA, were later served by Mexican evangelists trained in various Bible schools.