San Francisco Xavier de Horcasitas, the first of three San Xavier missions, which also included San Ildefonso and Nuestra Señora de la Candelaria, was established by the College of Santa Cruz de Querétaro under the recommendation of Father Mariano Francisco de los Dolores y Viana. It was located on the San Gabriel River (then known as the San Xavier) about five miles from the present site of Rockdale in Milam County. The impetus for the mission came in June 1745 when a group of Indians, including members of the Yojuane, Deadose, Mayeye, and Ervipiame groups, came to San Antonio de Valero Mission to ask Father Dolores to establish a mission for them in their own territory. The priest persuaded the commissary visitor, Father Francisco Xavier Ortiz, to petition the College of Santa Cruz de Querétaro for support of the mission project. Aside from converting a new group of Indians, the missions would stop apostates from San Antonio missions from taking refuge with those Indians and would help break Indian commerce with the French. In the winter of 1745 Dolores set up a temporary mission, known as Nuestra Señora de los Dolores del Río de San Xavier, with support from the college. Ortiz traveled to Mexico City on behalf of the college to get necessary viceregal sanction and financial support for the mission project. After a protracted debate over location of the missions, Viceroy Francisco de Güemes y Horcasitas, Conde de Revilla Gigedo, sent his permission and financial assistance for official establishment of the San Xavier missions on the site selected by Dolores y Viana. San Francisco Xavier Mission was founded on the south bank of the San Gabriel River in February 1748 by Father Dolores. It served the Yojuane, Mayeye, Ervipiame, Asinia, Top, and Nabedache groups.
Missionary work suffered as a result of conflict between the missionaries and military authorities. The temporary detachment of thirty soldiers proved inadequate to ward off the frequent Lipan Apache attacks on Mission San Francisco. Royal officials in Texas refused to cooperate with the missionaries by sending additional troops. The College of Santa Cruz de Querétaro finally urged Viceroy Revilla Gigedo to establish a presidio to guard the missions. While investigating possible sites for building a presidio in the summer of 1750, Capt José Joaquín de Ecay Múzquiz found 153 Indians at Mission San Francisco Xavier and noted that seventy-seven baptisms had been performed since 1748. Conditions deteriorated after San Francisco Xavier de Gigedo Presidio was formally established in 1751. The missionaries complained about a lack of cooperation and immoral behavior of the soldiers and their commander. In 1752, an attack on sister mission Candelaria, which resulted in the deaths of a missionary and a soldier, further undermined morale. A drought and an epidemic also plagued the missions between 1752 and 1755. Despite these hardships, Capt. Pedro de Rábago y Terán, the new presidio commander in 1754, discovered seventy Mayeyes and Ervipiames still at San Francisco Xavier de Horcasitas Mission. Unhealthy conditions along the San Gabriel eventually drove Rábago to move the presidio and the missions without waiting for authorization. He pulled back to the San Marcos River in August 1755. Shortly thereafter more than 1,000 Lipan Apaches joined the missionaries. The San Marcos site could not support such a gathering of Indians, and in 1756 all property from the San Xavier missions and the presidio were reassigned to Santa Cruz de San Sabá Mission, which would serve the Apaches in their own territory. The neophytes from Mission San Francisco Xavier de Horcasitas were sent to the San Antonio missions, with the exception of the Mayeyes, who persuaded the missionaries to build them a separate mission on the Guadalupe River. It lasted only two more years (see SAN FRANCISCO XAVIER MISSION ON THE GUADALUPE RIVER).
Archeological work was done by Kathleen Gilmore in 1967 at H. E. Bolton's proposed location of the site of San Francisco Xavier Mission. Indications of jacal walls, burials, Spanish colonial ceramics and glass, and Indian pottery and projectile points were found. Limited archeological testing in 1983 by Gilmore and Harry Shafer at the presumed site of the garrison living area recovered Spanish colonial ceramics, horse trappings, Indian ceramics, and daub (sun-dried mud plaster).