Medellin National Science and Technology School (MNSTS) was formally established in 1996 following a municipal resolution calling for the creation of a science high school in Poblacion, Medellin, Cebu. Before securing a permanent site, the school was known as the National Science and Technology School of Medellin and initially operated at Medellin Central School due to the lack of facilities.

Classes began in June 1995 with only one teacher, Mr. Joel S. Comendador, a physics instructor. A few months later, Mrs. Neriza Seares joined, and together they handled a small student population of 23 first-year and 30 second-year students. Without dedicated classrooms, students had to study under trees or sit on makeshift wooden boards. Despite these challenges, the school remained committed to providing a strong foundation in science and technology education.

Recognizing the urgent need for a permanent school site, the Local Government Unit (LGU) of Medellin, led by Mayor Manreza P. Lim, collaborated with former Bogo Mayor Clavel A. Martinez to secure land and funding. A lot in New Medellin Estate Subdivision was donated, enabling the Department of Public Works and Highways (DPWH) to construct five school buildings. By January 2000, the school officially transferred to its new location with a small but dedicated faculty.

In 1999, MNSTS shared its campus with Medellin National Science and Technology Elementary School (MNSTES), Medellin National High School (MNHS), and Cebu Normal University-Medellin Campus (CNU). As the school grew, the LGU of Medellin donated an additional 2,500 square meters of land in 2012, allowing for further campus expansion. Later, through a Deed of Usufruct signed by Mayor Joven J. Mondigo Jr., a 753-square-meter site was granted for the Senior High School Department, ensuring more space and facilities for STEM students.