The institute's first principal was Hamilton Hatter. The first president of the board of regents was Nathan Cook Brackett, an abolitionist who had earlier served as the first president of Storer College in Harpers Ferry. State Senator William Mahood, a Mercer County Republican, had written the sponsoring legislation, and the institute's administrative building was named for him. Hatter oversaw construction of Mahood Hall and the dormitories Lewis Hall and West Hall. In 1906 Robert P. Sims, who would lead the school for the next three decades, succeeded Hatter. The institute added teacher training in 1909, expanded to 23 acres, added Payne and Conley Halls, and watched enrollment climb past 600 on what students called the terraced hills. The President's House, built in 1930 and later renamed Hatter Hall, is on the National Register of Historic Places.

In 1932 the State of West Virginia accredited the education curriculum and changed the name to Bluefield State Teachers College. In 1943 a further accreditation and curriculum expansion produced the simpler Bluefield State College. Henry Dickason, an institute alumnus, served as president from 1936 to 1952 and shepherded the school through the Depression and World War II. The football teams, then called the Blue Devils, had won Negro College Athletic Association national championships in 1927 and 1928. The institute competed in the Colored Intercollegiate Athletic Association — the conference that later became the Central Intercollegiate Athletic Association, the oldest historically Black athletic conference in the country — from 1932 through 1955.

After the 1954 Brown v. Board of Education decision, Bluefield State began admitting white students. By the late 1960s, African American students were protesting that the administration was deliberately transforming the school from a residential historically Black college into a commuter campus with a predominantly white student body. The tension boiled. On November 21, 1968, a bomb exploded in the gymnasium. No one was injured but the damage was extensive. Governor Hulett C. Smith offered a $5,000 reward. College president Wendell Hardway responded by closing every dormitory on campus immediately and permanently. Students returning from Thanksgiving break found themselves locked out of housing they had paid for. The action accelerated the school's transition. By the 1980s Bluefield State was, in the words of an NPR feature, the whitest historically Black college in America.

In 2003 the West Virginia Legislature created a new community college system. Bluefield State was required to transfer all of its two-year programs, except engineering and nursing, to the newly created New River Community and Technical College — and lost roughly half of its enrollment in the process. In 2020, under President Robin Capehart, the college acquired the former Bluefield Regional Medical Center: 68 acres of property, hospital rooms converted to dormitories, a cafeteria and lounge spaces ready by fall 2021. For the first time since the locked-out students of 1968, Bluefield State was a residential campus. Football returned in 2021 after a 41-year absence under coach Tony Coaxum. In 2023 the team rejoined the CIAA, competing again against other historically Black colleges for the first time in seventy years. President Capehart retired in 2023 after a Higher Learning Commission peer review harshly criticized his governance and that of the board of governors for actions including disestablishing the Faculty Senate and making academic changes without faculty involvement. The school continues, now a university, still a member of the Thurgood Marshall College Fund, still on its terraced hills.