Nuestra Señora de Guadalupe Mission was part of the missionary complex that grew up at a Polacme Indian village near the confluence of the Rio Grande and Río Conchos. Sixteenth-century explorers such as Antonio de Espejo called it Santiago. Their early expeditions referred to it as the largest of the pueblos at La Junta de los Ríos del Norte y Conchos. In 1670 missions were tentatively begun in the area, but no detail concerning them has survived. Fray Miguel de Menchero, in his recounting in 1744 of missionary activity at La Junta, stated that these early attempts were short-lived. It was not until 1683 that missions were established on a permanent basis. In that year Juan Sabeata, chief of the Jumano and Cíbola Indians at La Junta, appeared at El Paso, leading a delegation asking that the Spaniards establish missions in their pueblos. When they appeared to demur, the Indians told of the miraculous appearance of a cross over their pueblos. Later the Spaniards found the story to be a fabrication of a Tejas Indian accompanying Sabeata. At the time, however, the custodian of religious at El Paso agreed to send missionaries on the condition that the Indians build a church and living quarters to accommodate them. On the following day, members of the Indian delegation sent messengers to take measurements of the altar at the church at El Paso. They gave orders to build religious establishments at La Junta based on this prototype. Within twenty days these messengers returned with more than sixty men and women to report that all available hands were employed in building two churches. On December 1, 1683, Franciscans Nicolás López, Juan Zavaleta, and Antonio Acevedo and their escort began a journey from El Paso that took thirteen days to reach La Junta. Upon their arrival at the first pueblo they found a large church reportedly made of glass with an altar constructed according to the measurements taken by the messengers. Several other churches at pueblos close by had also been completed. Presumably Guadalupe Church was of the same construction but not to the missionaries' liking, for after saying Mass at the first pueblo, López and the others moved on and found a more well-constructed church and living quarters at the pueblo of Julimes.
In July 1684, as a result of raids by Spanish slavers, Indians at La Junta rose in revolt. Christian Indians and missionaries fled to Parral. The missions reopened later in the year. The missionaries at La Junta fled once again in 1688 during another uprising. In 1693 four missionaries were named for service at La Junta. Later, in 1715, when Juan Antonio Trasviña y Retis visited the area, he found the churches built at the missions, including the one at Guadalupe, in great need of repair. He ordered these churches, originally jacals built of sticks and thatch, rebuilt out of adobe. Nuestra Señora de Guadalupe was among the six missions reestablished at the time of the Trasviña y Retis entrada, when it was first called by that name. Although Trasviña y Retis claimed that the population of the mission was 550, that figure has been challenged in modern scholarship. It has been argued that Trasviñas figure included Indians visiting at Guadalupe from neighboring pueblos and that a more accurate count for this pueblo would be 191. Two missionaries, Fray Gregorio Ramírez and Fray Juan Antonio García, accompanying Trasviña y Retis remained to minister at La Junta, and six more were sent the following year. Each mission at La Junta was apparently to have its own missionary. Early in 1718 the Indians again were in revolt, and the missionaries fled from La Junta. They returned by the end of the year. Intermittently, from 1718 through the 1720s, missionary activity at La Junta was curtailed due to unrest among the Indians. Conditions in the region led to a proposal that a presidio be built there. In 1727 the viceroy suspended the order for such a presidio for lack of funds. With conditions among the pueblos at La Junta unstable, missionaries no longer resided permanently at the missions but began visiting their converts there for only a short time each year. These missionaries spent the remainder of the year in Chihuahua. One of three expeditions sent in 1747 to examine the area at La Junta, overrun by enemy Apaches, found it partially abandoned, as it had been for about twenty years. A presidio was needed to stabilize the situation and allow for peaceful settlement and resumption of more permanent missionary activity.
The three expeditions that visited La Junta in 1747 were led by Capt. Joseph de Idoyaga (Ydoyaga) of San Bartolomé, Capt. Fermín Vidaurre of the Presidio de Mapimí, and Governor Pedro de Rábago y Terán of Coahuila. Idoyaga found Fray Francisco Sánchez in residence at Nuestra Señora de Guadalupe. He ministered to visitas, or smaller satellite congregations, at San Cristóbal and Los Puliques. Vidaurre gave the population at Guadalupe Mission as 172 and listed Fr. Lorenzo Saavedra as missionary. Rábago y Terán arrived toward the end of the year and was well received at Nuestra Señora de Guadalupe. The church building must have been somewhat substantial, for on December 19 the governor and all his men attended a Mass of thanksgiving there.
In 1759 a company led by Capt. Rubín de Celís came to build the long-awaited presidio at La Junta. Scholars locate the presidio, like the original site of Guadalupe, on both the Texas and Mexican side of the Rio Grande. Some sources claim the presidio was at the site of Fort Leaton. Others claim it was at the pueblo of Nuestra Señora de Guadalupe. A related controversy concerns the crossing of Trasviña y Retis from San Francisco de la Junta Pueblo to Nuestra Señora de Guadalupe. Some explorers and some historians of the original account claim that the river crossed was the Río Conchos, but others, notably J. Charles Kelley, argue that the river crossed was the Rio Grande. Since Trasviña did not specify which river he crossed, the question is still open to debate. On July 22, 1760, a fiesta was held to celebrate the presidio's completion. A number of Apache and other Indians camped nearby, purportedly to join in the celebration. They attacked the presidio at sunrise but were beaten back. After the battle Lt. Narciso Tapia was sent across the river to fetch a priest and saw the missionaries come out of the chapel there. This chapel is identified as that of the Mission of Nuestra Señora de Guadalupe.
By 1767 the presidio was abandoned and its force moved from La Junta to Julimes. In the 1770s Hugo Oconór ordered the presidio again established at La Junta. The Presidio del Norte remained until 1835. The year 1794 saw six missions still in operation at La Junta. However, by 1795, as a result of the policy of secularization, only two remained, at Julimes and Tapalcolimes. In 1830 the village earlier known as Guadalupe, now Presidio del Norte, became a port of entry. Between 1832 and 1838 a grant comprising much of the La Junta area changed hands several times, finally coming to the Leaton family. By 1863 the name of Presidio del Norte was changed to Ojinaga in honor of the patriot Manuel Ojinaga, who resisted French occupation of Mexico. It is generally accepted today that the church and other structures of the pueblo of Nuestra Señora de Guadalupe are beneath the site of present-day Ojinaga, Chihuahua, Mexico.