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).

In the fall of 2015, Medical Academy relocated to a new facility in Olmito, across the expressway from Rancho Viejo. At the same time, the district opened Rising Scholars Academy of South Texas (Rising Scholars Academy), its second middle school, in the facility that formerly housed Medical Academy in San Benito. In the initial school year (2015-2016), the campus served 7th-graders. It phased in its second grade level the following year, and is now serving 7th- and 8th-grade students. 

In 2019, BETA underwent a program change and name change to become South Texas ISD World Scholars (World Scholars, for short). Through the program change, the campus will expand its International Baccalaureate (IB) course offerings and continue to offer Dual Enrollment in partnership with South Texas College (STC) and The University of Texas Rio Grande Valley (UTRGV).

In the same year, the district also went through a re-branding process, which resulted in slight name changes (and updated logos) for the campuses to better reflect each school as part of STISD. Below are the updated campus names:
South Texas ISD Health Professions
South Texas ISD Medical Professions
South Texas ISD Preparatory Academy
South Texas ISD Rising Scholars Academy
South Texas ISD Science Academy
South Texas ISD World Scholars

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.