The University of Oklahoma was founded upon authority of an act of the first legislature of the Territory of Oklahoma seventeen years before statehood. Approved in 1890 and adopted in its main provisions by the first legislature of the state in 1907, the act stated the purpose of the University was to "provide the means of acquiring a thorough knowledge of the various branches of learning connected with scientific, industrial, and professional pursuits". The town of Norman was selected for the university. Students were accepted for the first time in the fall of 1892, and the first two graduates of the University received the degree of Pharmaceutical Chemist in 1896.

At the turn of the twentieth century, the College of Medicine was founded as a two-year preclinical school. Ten years later in 1910 it merged with the Epworth Medical College in Oklahoma City and became a four-year degree-granting school. In 1911 the first degree in medicine was awarded.

Under the direction of the College of Medicine a two-year School of Nursing was organized in 1911. In 1913 the school graduated its first class and became a three-year diploma program. Future physicians and nurses trained in the old Rolater Home and Hospital in Oklahoma City until 1919 when University Hospital was built. Children's Hospital of Oklahoma was completed in 1928 and became the second state-owned University of Oklahoma hospital. In the interim, construction had begun on a new College of Medicine building, and by 1928 it was possible to centralize all of the College's preclinical and medical operations.

During the ensuing years enrollment climbed steadily, a Graduate College was formed, and new health facilities were added to help meet the comprehensive health-care needs of the state. The Veterans Administration Hospital and the privately sponsored Oklahoma Medical Research Foundation were constructed. In 1957, the School of Nursing was authorized to confer baccalaureate nursing degrees.

In 1967, a School of Health was established at the Center. The school was accredited by the American Public Health Association in June of the same year. It admitted its first class of students in January 1968 and thus became one of eighteen accredited Schools of Public Health in the nation. The school later took the name College of Health. Also in 1967 the School of Health Related Professions was approved and in 1970 it was activated for the purpose of integrating, correlating and coordinating the several allied health programs already existing in the medical center, and those which would develop in the future. In 1971 the school became the College of Allied Health Professions. In 1973 the College of Health and the College of Allied Health Professions were joined together. In 1981 they were again separated and the College of Allied Health and the College of Public Health were formed.A Dean was appointed for the College of Dentistry in 1969, and three years later the college's first class was accepted and began studies. In 1971, the University of Oklahoma Medical Center became the University of Oklahoma Health Sciences Center and all schools on the HSC campus were designated as colleges. In 1976, the Colleges of Medicine, Nursing, Health, and Dentistry and the Graduate College were joined in Oklahoma City by the College of Pharmacy, the oldest academic unit at the University of Oklahoma.

Established in 1972, the College of Medicine-Tulsa has enabled the University to use hospital training facilities in Tulsa to establish medical residencies and provide for expanded health care capabilities in the state. Under this program, selected third- and fourth-year students receive their clinical training in hospitals in the Tulsa community.

In 1973, Oklahoma's legislature provided for the creation of a board of trustees to operate and govern University Hospital and transferred Children's Memorial Hospital to the Department of Institutions, Social and Rehabilitative Services. The hospital's name was later changed to Oklahoma Children's Memorial Hospital and again in 1987 to Children's Hospital of Oklahoma. In 1980, University Hospital was transferred to the Department of Human Services changing the name to Oklahoma Memorial Hospital. On July 1, 1993, the Oklahoma Medical Center was transformed into The University Hospitals, and the institutions became an independent state agency after Senate Bill 423 separated the hospital complex from the Department of Human Services. Under the bill, Oklahoma Memorial Hospital's name was changed to University Hospital. The hospitals, governed by the University Hospitals Authority, provide medical facilities to OU and other higher education institutions throughout the state. This grouping of seven health-related colleges, located in a fifteen-block area near the state capitol, and the Tulsa Medical College, located in the state's second-largest metropolitan area, is known today as the University of Oklahoma Health Sciences Center. The University is accredited by the North Central Association of Colleges and Secondary Schools.