After asking for President Thomas Humes' resignation in 1883, the Board of Trustees did not immediately name a new leader. The office remained vacant for nearly five years before the Trustees appointed Charles William Dabney (1855-1945) President in 1887. He was the first President to hold a PhD and did much to make the century-old institution on the Hill a university in fact as well as in name. He built a research institution with new laboratories, dormitories, a gymnasium, a library, and further developed the College of Agriculture. He re-organized the faculty and in 1893 women were officially admitted to the University. The Summer School of the South was also implemented during his tenure.

Brown Ayres (1856-1919) replaced Dabney in 1904 and continued to expand the University. During his fifteen year administration Ayres created the colleges of Law, Medicine, and Dentistry, oversaw the building of the Carnegie Library (1911), raised entrance requirements, obtained the University's first appropriation from the state legislature, reorganized the Board of Trustees to include gubernatorial-appointed members from the entire state, provided scholarships based on electoral districts, moved the Medical and Dental colleges to Memphis, and enlarged the Agricultural College to meet the needs of rural families in all parts of Tennessee.

Ayres died suddenly in 1919 and was replaced by Harcourt Alexander Morgan (1867-1950), an agricultural expert and Dean of the Agricultural College. As president, Morgan emphasized UT's role in statewide affairs, arguing that "the entire state is its campus," with farms, factories, schools, and homes included in the University's services and responsibilities. With the help of the state legislature, Morgan managed to secure significant funds for new buildings on the Knoxville campus, including an engineering building, two women's dormitories, and Shields-Watkins field. Morgan's political savvy and concern for the financial fortunes of the University led him to exercise caution with respect to those issues which he publicly supported or opposed. In 1925 the Tennessee legislature passed a bill forbidding the teaching of evolution in public schools. Many people believed that because of his statewide popularity, UT's president could have influenced the debate and prevented the act from becoming law. Morgan feared, however, that a public stance one way or the other would jeopardize legislative funding for the University, and declined to take a public stand. In a similar matter Morgan declined to intervene in the dismissal of seven UT faculty members, despite his own reservations about the propriety of the actions, because he did not want to come into open conflict with the deans who had recommended the action. Morgan left in 1933 to take a position as one of three board members on Franklin D. Roosevelt's Tennessee Valley Authority.

Morgan's successor was James Dickason Hoskins (1879-1960), a professor of history and economics, dean of the University, and acting president on two separate occasions. As dean and president, he witnessed an explosion of new physical facilities, including Ayres Hall (1921), Sophronia Strong dormitory (1925), the Home Economics Building (1926), Dabney Hall (1928-1929), the Physics and Geology Building (1928), Ferris Hall (1930), the Library (1931), Henson Hall (1931), the Alumni Memorial Gym (1934), the Hesler Biology Building (1935), and Melrose Hall (1946). During his presidency, Hoskins reiterated a suggestion first made by President Harcourt Morgan in 1922 that a regular faculty retirement plan be instituted, and in 1941 the plan was finally implemented. Under Hoskins's leadership, the University weathered the Great Depression and World War II. By the end of that conflict, Hoskins was seventy-six years old, and in June 1946, he finally retired. He retained an office on the campus, continued to be visible, and worked on a history of the University. In 1950, the library that had been built while he was dean was named after him.