The Salkehatchie campus was established in 1965 as a regional center of the University of South Carolina as the result of local civic commitment and momentum. In late 1964, a group of residents from Allendale, Bamberg, and Hampton counties organized a movement to create a regional campus. The General Assembly of South Carolina responded the next year by creating the Western Carolina Higher Education Commission, which is composed of two Governor-appointed representatives from each of the participating counties. Barnwell County later joined the compact and Colleton County followed in 1984. The campus was given the name Salkehatchie because the Salkehatchie River runs through all five counties that support the campus.

The first building for the campus was a former elementary school in Allendale. Since that time, the campus has expanded to 14 buildings on two sites and possesses over 220 acres. In 1979 classes began on the Walterboro campus, followed by the 1981 acquisition of the Main Classroom building and gymnasium. Also in 1981, the new Science and Administration building was opened on the Allendale campus. Several other acquisitions followed, culminating with the construction and opening of a Learning Resources Building in Allendale in 1991. More recently, USC Salkehatchie has acquired two buildings in close proximity to the Walterboro campus to be used for science labs and offices. Future construction includes a new Science and Technology Center on the Allendale campus to house science laboratories, administrative offices, and special programs such as the Salkehatchie Health Collaborative.

The academic program was initiated in the fall of 1965 with eight part-time faculty and 76 students. Today, over 900 students enroll each term and are taught by twenty full-time faculty. Since 1965 USC Salkehatchie has provided opportunities in higher education to hundreds of students who are placebound or desire to attend college closer to home. As the campus has grown, so has its educational, cultural, and economic impact on the community. Salkehatchie expects to continue to play an important part in the lives of local citizens as the institution enters its fifth decade of service to the rural lowcountry.