North Carolina Central University was chartered in 1909 and opened its doors to students in 1910 as the National Religious Training School and Chautauqua. Dr. James E. Shepard, the founder, served as the President of the institution from its founding until his death in 1947. From the beginning, North Carolina Central University has declared its purpose to be the development in young men and women of the character and sound academic training requisite for real service to the nation.

The institution's early years were characterized by a wealth of enthusiasm and high endeavor, but not of money. Private donations and student fees constituted the total financial support of the school and the heavy burden of collecting funds rested on the President. A consequence was the sale and reorganization of the school in 1915 as the National Training School. During this period of its history, Mrs. Russell Sage of New York was a generous benefactor of the school. In 1923, the General Assembly of North Carolina appropriated funds for the purchase and maintenance of the school, which thus became a publicly-supported institution as Durham State Normal School. Two years later, the General Assembly redefined the mission of the school, naming it the North Carolina College for Negroes and dedicating it to the offering of liberal arts education and the preparation of teachers and principals of secondary schools. North Carolina College for Negroes (NCC) thus became the nation's first state-supported liberal arts college for African American students.

At its 1927 session, the General Assembly began a program of expansion of the college plant, with the support of Angus W. McLean, then the Governor of North Carolina. State appropriations were supplemented by a generous gift from B.N. Duke, a Durham philanthropist, and by contributions from other citizens of Durham in 1929. The 1930's afforded federal grants and State appropriations for further physical expansion and improvement ofr educational facilities, with building continuing until the beginnings of World War II. North Carolina College was accredited by the Southern Association of Colleges and Secondary Schools in 1937 as an "A" class institution. The institution was admitted to membership in the association in 1957.

The General Assembly of 1939 authorized the establishment of graduate study programs in liberal arts and the professions. Graduate courses in the Arts and Sciences were offered that year, while the School of Law began operation in 1940, and the School of Library Science was established in 1941. In 1947, the General Assembly changed the name of the institution to North Carolina College at Durham. In October, 1947, Dr. Shepard, the founder, died. Following his death, the college was administered by an interim committee consisting of Dr. Albert E. Manley, Dean of the College of Arts and Sciences; Miss Ruth G. Rush, Dean of Women; and Dr. Albert L. Turner, Dean of the School of Law. The interim committee served until the election as President, on January 20, 1948, of Dr. Alfonso Elder, who headed the Graduate Department of Education and had previously been Dean of the College of Arts and Sciences. Dr. Elder, whose tenure also saw substantial physical expansion of the college, retired as President on September 1, 1963, and was succeeded by Dr. Samuel P. Massie, then Associate Program Director for Undergraduate Science Education of the National Science Foundation. Dr. Massie was also Professor and Chairman of the Department of Pharmaceautical Chemistry at Howard University at the time of his election as President of North Carolina College.

When Dr. Massie resigned on February 1, 1966, the administration of the college was assumed by a second Interim Committee, whose members were Mr. William Jones, Business Manager; Dr. Helen G. Edmonds, Graduate Dean; and Dr. William H. Brown, Professor of Education. The interim committee served until July 1, 1967, when Dr. Albert N. Whiting assumed his duties as President. Dr. Whiting, who had been elected President by the Board of Trustees on July 20, 1966, was Dean of the Faculty of Morgan State College at the time of his election. He served as President and Chancellor of the institution until his retirement June 30, 1983. North Carolina College at Durham became North Carolina Central University in 1969. Among the significant developments during Dr. Whiting's 16 years of service was the creation of the NCCU School of Business. Programs in public administration and criminal justice were also launched during those years.

A momentous development in the history of higher education in North Carolina came on July 1, 1972, when the state's four-year colleges and universities were joined with the branches of The Consolidated University of North Carolina. The reconstituted University of North Carolina, with 16 individual campuses, was headed by a single President and governed by the University of North Carolina Board of Governors. The Presidents of the institutions which had previously been under the oversight of the North Carolina Board of Higher Education assumed the title of Chancellor, which had previously been the title of the institutional heads of UNC campuses in Chapel Hill, Raleigh, Greensboro, Charlotte, and Wilmington.

Dr. Whiting was succeeded as Chancellor by Dr. LeRoy T. Walker in the role of Interim Chancellor. Dr. Walker had served the institution as Chairman of the Department of Physical Education and Recreation, Head Track Coach, and Vice Chancellor for University Relations. He had served as the United States' head track and field coach at the 1976 Olympic games, and was a key administrator in the early years of the U.S. Peace Corps. At their February, 1986, meeting, the University of North Carolina Board of Governors, at the request of NCCU's Board of Trustees, retroactively awarded Dr. Walker the title of Chancellor, effective as of the beginning of his term in 1983.

Dr. Tyronza R. Richmond, formerly Dean of the School of Business, succeeded Dr. Walker as Chancellor on July 1, 1986. Prior to his arrival at NCCU, Dr. Richmond was Associate Dean and Professor at the School of Business and Public Administration at Howard University. Dr. Richmond's tenure saw the creation of the School of Education (formerly the Department of Education) and a reorganization of the academic administrative structure. Dr. Richmond resigned as Chancellor to return to the classroom and was succeeded on January 1, 1992, by Dr. Donna J. Benson as Interim Chancellor.

Dr. Benson was succeeded on January 1, 1993, by Julius L. Chambers, who resigned the post of director-counsel (chief executive) of the NAACP Legal Defense and Education Fund. Chancellor Chambers, a distinguished civil rights attorney for over a quarter-century, was the first alumnus of the institution to serve as its chief administrator, having received his bachelor's degree in history in 1958. Chancellor Chambers launched a major capital construction effort, still in progress, with substantial renovations at all student residence halls and most classroom facilities, and construction of an additional residence facility on the site of the existing Chidley Hall, a Biomedical/Biotechnology Research facility, and a new School of Education.

James H. Ammons, the ninth chief administrator of North Carolina Central University (NCCU), became Chancellor June 1, 2001. He received the bachelor’s degree from Florida A&M University in political science in 1974 and the master’s degree in public administration in 1975 from Florida State University. At the age of 24, Dr. Ammons completed the requirements for a doctorate in government in 1977 from Florida State University. Prior to serving as chancellor, he was provost and vice president of Academic Affairs at Florida A&M University where he developed more than 22 bachelor’s, master’s and Ph.D. degree programs.