The district was created in 1964 by the Texas legislature to provide education to disabled youth who were then excluded from public education. It was known as Rio Grande Rehabilitation District until 1973 and renamed South Texas Independent School District (STISD) in 1974.

STISD started as a residential school in Edinburg, named South Texas High School. To better accommodate the students of the lower Rio Grande Valley, STISD opened another school by the same name in Harlingen in 1967. In 1982, STISD moved the Harlingen school to a new facility in San Benito.

Lawmakers extended STISD’s purpose in 1983 to encourage the operation of vocational magnet schools. Soon after, South Texas High School for Health Professions (Med High) opened in Mercedes in 1984. It was followed by The Science Academy of South Texas (Sci Tech), also in Mercedes, in 1989.

In 1993, South Texas High School in Edinburg was redirected and reopened as The Teacher Academy of South Texas (Teacher Academy).

In 2003, Teacher Academy added business and technology programs and the school was renamed South Texas Business, Education & Technology Academy (BETA). That same year, South Texas High School in San Benito was redirected and reopened as South Texas Academy of Medical Technology (Med Tech).

In 2008, the junior high from South Texas Business, Education & Technology Academy (BETA) separated and opened as South Texas Preparatory Academy (STPA).

Though the district’s mission has evolved since 1964, STISD continues to provide educational and occupational training to students with special needs through the Half-Day Career & Technology Program offered at each school.

In the fall of 2015, Medical Academy will be relocating to a new facility in Brownsville, across the expressway from Rancho Viejo. At the same time, the district will open its second middle school in the facility that currently houses Medical Academy in San Benito. The new middle school will serve 7th- and 8th-grade students; however, only 7th-graders will be enrolled for the initial 2015-2016 school year.