[7] In 1866, facing a cholera outbreak in Galveston immediately after the Civil War and unable to summon help from American congregations, Bishop Claude Dubuis called religious sisters from France to nurse the sick.

In 1869 Dubius nominated three sisters to start a San Antonio congregation, which subsequently established an infirmary (later to become Christus Santa Rosa Hospital), an orphanage, and a school.

[8][9] In July 1881 the Sisters of Charity of the Incarnate Word, with a charter from the State of Texas, first opened a schoolhouse for girls on Avenue D which later moved and in 1893 grew into St. Patrick's Academy, considered the forerunner to IWHS and also located on Government Hill.

[15] In the early 1970s, the high school incorporated modular scheduling[a] and built its science building, a new library, and swimming pool.

[14] In 1978, despite resistance from Sisters of Charity of the Incarnate Word and the San Antonio Conservation Society, the Texas Highway Department constructed US 281 through Incarnate Word school, separating the high school from the college, with the Sky Bridge connecting the campuses as the sisters stipulated.