It was founded by the Jesuits in November of the year 1705.

It was established in a region that the Cochimí people called Mulegé, which means 'White Mouth Canyon.'

The construction was funded by the Marquis of Villapuente, and the project was overseen by Father Juan Manuel Basaldúa following the instructions of Juan María Salvatierra. Like in other cases, the initial constructions were adobe structures. 

A year later, Father Basaldúa was replaced by Father Francisco María Piccolo, who led the mission until 1718. He was succeeded by Father Sebastián Sistiaga until 1727 and Juan Bautista Luyando until 1734.

In 1766, Father Francisco Escalante completed the construction of the mission in stone, and the mission became a starting point for the establishment of the missions of San Ignacio and La Purísima.

It was abandoned in 1828 due to lack of population; however, the old Mission was restored and is used as a church.