Mindanao State University-General Santos started as a community high school in 1967, six years after the creation of MSU- Marawi Main Campus.  The high school was hosted inside Dadiangas West Elementary School, a school located in the middle of General Santos City. To accommodate the growing number of students, the administration facilitated the approval of 3.3 hectare land donation of General Santos City Local Government located at the heart of General Santos City for the MSU-High School. By virtue of the Board of Regents Resolution No. 822, it became a full pledged collegiate campus of the MSU System on October 10, 1973, offering two-year degree courses.

The 156-hectare land located at Fatima (previously part of Barangay Tambler) was acquired through Presidential Proclamation 2029 of 1983. This led to the growth of MSU offering various degree programs. Since then, MSU General Santos has been characterized by its continuing commitment and dedication to the communities it serves through its three functions: instruction, research and extension. The Fatima campus houses administrative offices, academic colleges: Agriculture, Education, Fisheries, Social Sciences and Humanities, Engineering, Business Administration and Accountancy, and other semi and non-academic units. Aside from undergraduate courses, post-baccalaureate degrees in Education, Public Administration, Business Management, and Law are being offered in response to the demand and needs of the teachers, government workers and other professionals in the locality. These are all offered in the MSU-CETD Campus as evening or weekend classes. Another campus is located in Bawing, General Santos City that serves as the field laboratory for the College of Fisheries.