The college was first conceived by local residents who petitioned the University of Virginia to establish a college in Wise. As support for a college grew, the Commonwealth of Virginia appropriated $5,000 to open, staff, and operate the college as a two-year junior college on a trial basis for a year; and if successful, another $5,000 would be available for a second year. In the winter of 1954, the local community matched the commonwealth's funds and collected over $6,000 to furnish the classrooms and use for supplies.Wise County donated over 400-acre (161.9 ha) of property that included two sandstone buildings, the property had once served as the county's poor farm. Clinch Valley College of the University of Virginia opened in September 1954 with an enrollment of 100 freshmen. Clinch Valley College became the westernmost state-supported college in Virginia and the only branch of the University of Virginia. Prior to its opening, Virginia lacked public colleges west of Radford.
Clinch Valley College operated as a junior college throughout the late 1950s and 1960s. During that time, the college gained more support from graduates who wanted to complete their baccalaureate degrees at the same institution and the college began the process to become a four-year college. In June 1970, Clinch Valley College granted its first Bachelor of Arts degrees; followed by Bachelor of Science degrees, first awarded in 1973. The college continued to grow and added new programs such as nursing and technology and in 1996, the college granted its first Bachelor of Science in Nursing degrees. In 1999, the Virginia General Assembly renamed the school "The University of Virginia's College at Wise," following an unsuccessful effort to change the institution's name in 1991. UVa-Wise expanded its focus on international education and signed three sister institution agreements along with initiating cooperative and mutual exchange programs for students and faculty with three international institutions in the late 1990s. In 1998, the college signed a sister institution agreement with Istanbul University. A year later, it signed a second agreement with another Turkish university, Dumlupinar University in Kütahya. In December 2000, the University of Seville in Spain became the college's third sister institution.
Through the early 21st century, UVa-Wise underwent rapid growth, with several new buildings and campus beautification projects to accommodate enrollment growth. As of September 2010, the college offered 31 majors, 31 minors and 23 teaching specialties and had an enrollment is about 2,005 students. On February 2, 2012, UVa-Wise saw the unexpected death of Chancellor David J. Prior. During his seven years as chancellor, the college experienced dramatic growth in student enrollment and facilities. During his tenure, the UVa-Wise's five-year fund raising campaign, known as the “Fulfilling the Dream” campaign, exceeded its goal to raise $50 million. UVa-Wise constructed numerous building during Prior's tenure, including the Hunter J. Smith Dining Commons, the Gilliam Center for the Arts and two residence halls, the $30 million Convocation Center, as well as the renovation of the Leonard W. Sandridge Science Center.
State lawmakers and regional leaders joined The University of Virginia’s College at Wise on July 1, 2009 to break ground for a $30 million Convocation Center, the largest single capital project in the College’s history. The facility seats 3,000 for sporting events and 4,000 for concerts or convocation activities. The facility provides the region with its first venue to seat large crowds, something economic developers have said is needed to boost growth and development in far Southwest Virginia. Shortly after the death of Chancellor David J. Prior in February 2012, the facilities were dedicated in his honor and named the David J. Prior Convocation Center.
The college requires all freshmen to enroll in a two-semester seminar that covers writing and adjusting to the demands of college academic work. The student's seminar instructor becomes his advisor until the student selects a major. The college also has a 53 semester-hour general education requirement. Students must attend four cultural activities in each their freshman and junior years. The college offers baccalaureate degrees in 31 majors. A College Major is also offered.
UVa–Wise teams, nicknamed athletically as the Highland Cavaliers, are part of the National Collegiate Athletic Association (NCAA), primarily competing in the Mountain East Conference. Men's sports include baseball, basketball, cross country, football, golf and tennis; while women's sports include basketball, cross country, golf, softball, tennis, lacrosse and volleyball. Carroll Dale, a former NFL football wide receiver, serves as assistant vice chancellor for athletic development. UVa–Wise has claimed conference titles in football, men's basketball, women's basketball, volleyball, softball, and baseball all within the past decade.