Mission Conference members, including Samuel Weston, Joseph Sasportas, and other prominent churchmen, played a crucial role in the December 18, 1869 founding of Claflin University. Boston philanthropist Lee Claflin and his son, Massachusetts Governor William Claflin, provided the initial financing for the purchase of the Orangeburg Female Academy, on whose grounds the new University was established. Dr. Alonzo Webster, who became Claflin's first president, and the Reverend T. Willard Lewis also played prominent roles in securing this site.

In 1871 Dr. Webster oversaw the merger of Claflin University and the Baker Biblical Institute, which was moved to Orangeburg. As a result of legislation in the South Carolina General Assembly, Claflin was affiliated with the South Carolina State Agricultural and Mechanical Institute (later to become South Carolina State University) from 1875 to 1896.

Since 1872, Claflin has been offering instruction in the arts and sciences, as well as in crafts and a variety of pre-professional fields. Teacher training has always been a vital aspect of the Claflin mission. The first class in the University's Normal Department (for teacher education) graduated in 1879. The College Department awarded its first bachelor's degree in 1882.

Reverend Edward Cooke served as Claflin's second president from 1872 to 1884. He was succeeded by Reverend Dr. Lewis M. Dunton (1884-1922), Dr. Joseph B. Randolph (1922- 1945), Dr. John J. Seabrook (1945-1955), Dr. Hubert V. Manning (1956-1984), and Reverend Dr. Oscar A. Rogers, Jr. (1984-1994). Dr. Henry N. Tisdale, a 1965 graduate of Claflin, became the University's eighth president on June 1, 1994.