The cathedral parish’s history began with the founding of the chapel of the Royal Presidio of San Agustin in Tucson, which was constructed in 1776. By the 1850s, both the presidio and its chapel had fallen out of use, so Father Joseph Machebeuf was sent to survey the condition of the area in the 1860s. He advised the Bishop of Santa Fe that a priest should be assigned to the location, which had a population of 600 people.
Father Jean B. Salpointe was appointed as pastor of the new church in 1866. Work on the structure—commonly referred to as a cathedral, even then—was completed by 1868. The Holy See declared the territory of Arizona an apostolic vicariate later that year, and Salpointe was appointed Vicar Apostolic.
The church was rebuilt by Bishop Peter Bourgade in 1897; the original plans called for a Gothic structure, but the spires were never completed. It was only in 1928 that the brick structure was transformed into its present Mexican baroque form, including the cast stone façade, which was inspired by the Cathedral of Queretaro, Mexico
A restoration project, which entirely demolished and rebuilt the cathedral with the exception of its façade and towers, coincided with the centenary anniversary of the completion of the original church. It was initiated in 1966 and completed in 1968.