The school was originally founded in 1888 as St. Paul's College under the supervision of the American Board of Commissioners for Foreign Missions (ABCFM) based in Boston, MA.  Education was carried out in the school's first building, Shepard Hall.  In 1911 Stickler Hall was completed, at the time it was the tallest building in Tarsus with its five stories.  Stickler is the symbol of Tarsus American College.

In its early years, the school was also called St. Paul's Institute and since 1930 the name has been solely Tarsus American College.  After the establishment of the modern Republic of Turkey in 1923, the government mobilized to improve, nationalize, and secularize education, including that provided by foreign schools. Turkish cultural lessons, taught by Turkish teachers, were added to the curriculum. The number of Turkish students, including Muslims, increased immediately. The school curriculum became secular, while the faculty continued to be a mix of American and local teachers.  TAC is now managed by the Health and Education Foundation (SEV), a Turkish non-profit foundation trust which also owns the school’s physical plant.  SEV was founded by the graduates of UAA, ACI, and TAC, referred to as the “SEV American Schools”, and Talas American Middle School in 1968.   The mission of the Health and Education Foundation is to insure the improvement and sustainability of its long established educational institutions which operate according to international standards and to raise individuals who exhibit a high level of academic performance and social awareness in response to a developing and changing world. 

Co-education started in 1979 with 35 girls joining the student body of 506 boys.  In 1986, the school graduated its first coed alumni class.  The same year, the boarding section, available from the preparatory class, was closed until its reopening for boys in 2002.   In 2008 boarding for girls began at TAC.