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. In 1863, Father Donato Rogieri arrived from Santa Fe, New Mexico, to the small village of Tucson of little more than sun-baked adobe homes near the Santa Cruz River, with no house of worship. After services were over, Father Donato and his parishioners would go to the Solano Leon place (where the Manning House is now at) and pick up adobe bricks and carry them back to the site of the church and one brick placed on top of another was how the walls were constructed. Work on the structure—commonly referred to as a cathedral, even then—was completed by 1868.
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 Querétaro, 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.