In 1692 Fr. Eusebio Francisco Kino, a Jesuit, came upon a tribe of Tohono O'odham during his travels. He built a mission church.

ln 1873, Bishop Salpointe asks the Sisters of St. Joseph of Carondelett to open a school near the San Xavier Mission Church to educate and help the poor community of the Tohono O'odham tribe. On September 2, 1873, five St. Joseph Sisters opened the school. The only subjects taught were Reading and Spelling.

In 1876, the school was closed and the Sisters moved to Sells, the Tohono O'odham capital.

It was not until 1888 that three Sisters of St. Joseph retuned to try to reopen the school. The Sisters continued to educate the Native American children on very limited resources, and their outreach to the families with medical supplies were very appreciated.

In 1910, the U. S. government began helping by paying the salaries and providing one meal a day for the students. (The school had been receiving funds from Mother Katharine Drexel up until this time.)

The Sisters of St. Joseph of Carondelett continued to teach at the school until 1932. Immaculate Heart Sisters came in 1930 and stayed until the Sisters of St. Joseph of Orange came in 1938. These Sisters stayed at the Mission School for two years.

In 1940, the Franciscan Sisters of Christian Charity arrived. That year the first day of school was September 5, 1940. Soon after their arrival it was determined that a new school needed to be built. The building was completed in 1947. It had two classrooms, a hall, and a stage. The convent to house the Sisters was located to the west of the school. In 1950, two more classrooms were added.

On August 27,1964, a tornado damaged the school, destroyed the convent, and destroyed two homes in the community. Unfortunately, three Tohono O'odham people were killed. Ever resilient, the convent was rebuilt, the school repaired and the Sisters continued to educate their students.

Kindergarten was added in 1981. It was determined in 1986 that the school needed some remodeling. The Fairfield Corporation of Tucson funded the renovations. Growth continued and a trailer was added in 1988. A bus was purchased in 1991 and because of increasing growth more renovations were completed in 1992 and 1993. In May of 1994 a new playground was donated by Iowa Equity insurance Company.

In 1999, it was determined that the school needed a new building. The community donations supported the project and ground was broken on May 10, 2000. Classes were held in mobile units until 2002, when the new school was opened. The new school had 9 classrooms, a modern kitchen, a hall, a library, a computer lab, and a parent meeting room.

The Franciscan Sisters of Christian Charity continue to teach at San Xavier Mission School and other religious and lay teachers now join them.