The school was founded by the Sisters of Charity of the Incarnate Word, who came to San Antonio in 1869 to assist with treating a cholera outbreak.

Sisters Madeleine Chollet, Pierre Cinquin, and Agnes Buisson had come at the request of Bishop Claude M. Dubuis.

The sisters traveled from Galveston to San Antonio by stagecoach, and once they arrived they discovered their new home had been destroyed in a fire.

This work in childcare led to the sisters opening up schools in Texas, Louisiana, Illinois, Missouri, and Mexico.

The campus stadium is dedicated to Tom and Gayle Benson who made generous donations that helped start the formation of the team.

In December 2013, a university policeman shot and killed Cameron Redus,[14] a student at UIW, nearby Alamo Heights during a traffic stop.

[16] Redus’ parents filed a wrongful death lawsuit against UIW in 2014, but university lawyers have continued to fight the family of the deceased insisting that the institution should be granted immunity.

Attorneys for the Redus family contend that as a private university, UIW does not receive public funds, and therefore would not qualify as a governmental entity.

[20] In July 2017, the UIW School of Osteopathic Medicine welcomed its inaugural class of 150 learners to its newly opened campus at Brooks on San Antonio's Southside.

The university's main campus is located in the Midtown Brackenridge district of San Antonio and the enclave city of Alamo Heights.

The Tom Benson Field House and Stadium, the Hillside II (later renamed Joeris) dormitory and the new Alonso Ancira Tower parking garage opened and were dedicated in fall of 2008.

[22] In 2013, as part of a larger strategy to build new arts facilities at the university, a new $16 million ceramics and sculpture studio was dedicated.

[26][27][28] In 2010, the UIW Men's Swim team placed second at the NCAA Division II National Championships in Canton, Ohio.

UIW is set to co-host the Final Four, the last 2 rounds of the NCAA men's basketball tournament with the University of Texas at San Antonio at the Alamodome in 2025.