Spring Hill College was founded by the first bishop of Mobile, Michael Portier. After purchasing a site for the College on a hill near Mobile, Bishop Portier went to France to find teachers and funds for the new college. Upon his return he rented a hotel next to the college grounds and started the first semester on May 1, 1830, with an enrollment of 30 students. On July 4 of the same year the bishop laid the cornerstone of the first permanent building. It stood on the site of the present Administration Building and opened for classes in November 1831. Spring Hill thus takes its place among the oldest colleges in the South. It is the third oldest Jesuit college in the United States.

In 1836 the governor of Alabama signed a legislative act which chartered the College and gave it “full power to grant or confer such degree or degrees in the arts and sciences, or in any art or science as are usually granted or conferred by other seminaries of learning in the United States.” This power was used in the following year, 1837, when four graduates received their degrees. The first two presidents of the College were called away to be bishops, one to Dubuque (Bishop Loras), the other to Vincennes (Bishop Bazin), and the third, Father Mauvernay, died after a brief term of office. Bishop Portier then found it necessary to transfer the College, first to the French congregation of the Fathers of Mercy, and next to the Congregation of Eudists, both of whom lacked teaching and administrative experience. He then persuaded the Fathers of the Lyons Province of the Society of Jesus to take possession of the College. The new regime was inaugurated with Father Francis Gautrelet, S.J., as president in September 1847. Since that time the institution has continued under Jesuit direction.

Instruction at the College was not interrupted by the Civil War, but in 1869 a fire destroyed the main building and required the removal of students and faculty to St. Charles College, Grand Coteau, Louisiana. Bishop Quinlan and other benefactors assisted in rebuilding the College, which reopened at Spring Hill before the year's end.

As the enrollment increased, Quinlan Hall, the College Chapel, the Thomas Byrne Memorial Library, and Mobile Hall were erected. In 1935, the high school, which had been a unit distinct from the College since 1923, was discontinued. In the space vacated by the high school, the Jesuit House of Studies was opened in 1937, and the Scholasticate of the Sacred Heart opened on a site adjoining the College a few years later. After World War II, a great influx of veterans taxed the facilities of the College, requiring the erection of a number of temporary buildings on the campus. At the request of Archbishop Toolen of Mobile, the College became coeducational in 1952. Black students were accepted into all departments of the College for the first time in 1954.