On March 7, 1887, the General Assembly of North Carolina enacted legislation, sponsored by Representative Hamilton McMillan of Robeson County, creating the Croatan Normal School. The law, which was in response to a petition from the Indian people of the area, established a Board of Trustees and appropriated $500 to be used only for salaries. Local people constructed a building at a site about one mile west of the present location.

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The school opened with 15 students and one teacher in the fall of 1887. The normal school was founded to train American Indian public school teachers. For many years, the instruction was at the elementary and secondary level, and the first diploma was awarded in 1905.

The school moved to its present location in Pembroke, the center of the Indian community, in 1909. The General Assembly changed the name of the institution in 1911 to the Indian Normal School of Robeson County, and again in 1913 to the Cherokee Indian Normal School of Robeson County. In 1926, the Board of Trustees added a two-year normal program beyond high school, and phased out elementary instruction. The first 10 diplomas were awarded in 1928, when the state accredited the school as a "standard normal school."

Additional college classes were offered in 1931, and in 1939, a fourth year was added with the first degrees conferred in 1940. In recognition of its new status, the General Assembly changed the name of the school in 1941 to Pembroke State College for Indians. Until 1953 it was the only state-supported four-year college for Indians in the nation. The scope of the institution was widened in 1942 when non-teaching baccalaureate degrees were added, and in 1945, when enrollment, previously limited to the Indians of Robeson County, was opened to people from all federally-recognized Indian groups. A few years later, in 1949, the General Assembly shortened the name to Pembroke State College.

The Board of Trustees approved the admission of white students up to 40 percent of the total enrollment in 1953 and, following the Supreme Court's school desegregation decision, opened the college to all qualified applicants without regard to race in 1954. Enrollment growth of over 500 percent followed during the next eight years. In 1969, the General Assembly changed the name again to Pembroke State University and made the institution a regional university. Such universities were authorized "to provide undergraduate and graduate instruction in liberal arts, fine arts, and science, and in the learned professions, including teaching" and to "provide other graduate and undergraduate programs of instruction as are deemed necessary to meet the needs of their constituencies and of the state."

In 1972, the General Assembly established the 17-campus University of North Carolina with Pembroke State University as one of the constituent institutions. The Board of Governors approved the implementation of master's programs in professional education at Pembroke State University in 1978, as well as several new undergraduate programs. Since that time, additional baccalaureate programs have been added, including nursing. Master's level programs have been implemented in Business Administration, Public Administration, School and Service Agency Counseling.

Pembroke State University celebrated its centennial in 1987. On July 1, 1996, Pembroke State University officially became The University of North Carolina at Pembroke.

In 2000, a major in applied physics and four new Master of Arts programs were added. An office of International Programs and the Esther G. Maynor Honors College were also instituted to enhance scholarship. Since then, the University has added new baccalaureate programs, including Spanish and environmental science, as well as new graduate degrees, including the Master of School Administration (M.S.A.) and the Master of Arts in Teaching (M.A.T.). Many classes at the undergraduate and graduate levels are available through distance learning at satellite locations in the region and via the Internet.

On July 5, 2005, North Carolina Gov. Mike Easley signed into law Session Law 2005-153, declaring The University of North Carolina at Pembroke as "North Carolina's Historically American Indian University."

Today, The University of North Carolina at Pembroke has approximately 6,900 students from diverse backgrounds. The University offers 41 undergraduate programs and 17 graduate programs.