Oklahoma City University began as "Epworth University", a project by local developer Anton H. Classen, who sought to begin a Methodist university in conjunction with other development projects. Construction began in 1902 and the school opened in 1904, three years before statehood, with an enrollment of 100 students. Anton Classen was heavily involved with development of early Oklahoma City and advanced the idea of a Methodist university in Oklahoma and helped spark the ideas of the Methodist Church to establish a Methodist university in Oklahoma. Construction began in 1902 and classes started in 1904 with enrollment growing by almost 100 students during that first year.

Epworth closed in 1911 after the school ran into financial difficulties. The church then formed "Methodist University of Oklahoma" in Guthrie, Oklahoma, which also absorbed a Methodist college in Texas, "Fort Worth University".[8] Eventually, the school's trustees developed a plan to close the school in Guthrie and reopen in Oklahoma City. The school opened in Oklahoma City as "Oklahoma City College" in 1919, bolstered by funding from Methodist congregations. The college experienced rapid growth and changed its name to Oklahoma City University in 1924. Despite the success and growth of the university in the 1920s, OCU again fell on hard times during the Great Depression.

Dr. Cluster Smith became president of Oklahoma City University after the Great Depression. When the United States entered World War II, the school faced new challenges, including mounting debt and a need for new facilities. Enrollment dipped during the war, as men left campus to enlist in the military. By 1942, the student body was 75 percent female. This created a shortage of players and funds causing many of the athletic programs, such as the football team, to end operations. After the war, enrollment increased dramatically and the university began a period of rapid development through the remainder of the 1940s. In the 1950s, OCU received accreditation from the North Central Association of Colleges and Secondary Schools. The university then took control of the Oklahoma City College of Law and began a partnership with the Massachusetts Institute of Technology to elevate the academics and the quality of education. The Bishop W. Angie Smith Chapel was dedicated in 1968 as part of a plan to expand OCU's spiritual life.