Founded in 1846 as the private University of Buffalo, UB began as a medical school. At first, classes were held in rented spaces in the city of Buffalo, until the first building was erected at Main and Virginia in 1849. The Schools of Pharmacy (1886) and Law (1887) were added, but it was not until the first liberal arts classes in 1913, and the official establishment two years later of the College of Arts and Science, that marks the establishment of UB as a true university.

At the same time, plans were taking shape to create a unified campus. Land was purchased (the current Main Street/South Campus) in 1909 and a major endowment campaign was held in 1920 to raise funds for building the campus. The campaign raised $5 million in 10 days in 1920. To give a measure of what was accomplished, it's the equivalent to about $60 million today. The addition of Samuel P. Capen as the first full-time Chancellor (1922-1950) further served to unify the once loose collection of professional schools under a centralized administration.

During his twenty-eight years at the University of Buffalo, Capen established many University programs and educational experiments that helped to further the expansion of higher education. He helped to broaden the education of the professional schools, developed standardized curriculums, and personally handpicked a first-class faculty of full-time, academically trained professors. He also established the Millard Fillmore College for adult education and created the Bureau of Personnel Research, a counseling office, to administer programs that tested the achievements and personalities of students in order to provide better guidance for career choices and help them obtain employment. The numbers attest to his role as administrator: student enrollment rose from 1,687 in 1922 to over 10,000 by the time of his retirement in 1950.

The explosion of enrollment after WWII came with a rapid expansion of academics. Clifford C. Furnas, chemical engineer, metallurgist, aviator researcher, and Olympic athlete, was the University's ninth chief executive, holding the position of Chancellor from 1954 until 1962 when the University merged with the State University of New York and his title changed to President. Furnas undertook an extensive program of expansion and enrichment to meet the growing educational needs of Western New York. He was the guiding force in the merger of the private UB with the State University of New York in 1962, affording an infusion of funding. Between 1961 and 1963, over 200 new faculty were hired to meet growing enrollment demand.

Likewise, UB's footprint expanded rapidly from the Main Street (South) campus to Amherst. The University at Buffalo's North Campus is located almost exactly in the center of the town of Amherst, NY approximately 3.5 miles from South Campus on the northeast edge of Buffalo, NY. In the mid-1960s, the University was quickly outgrowing its 178-acre campus, which was once the grounds for the Erie County Almshouse and County Hospital. After a few unsuccessful attempts to acquire land for a new campus in downtown Buffalo, the University looked to the surrounding suburbs. Then governor of New York Nelson Rockefeller helped the University acquire 2,000 acres in Amherst, and in October 1968, the University began the intensive planning for the newly acquired land.

Today, UB is the largest and most comprehensive research university in the SUNY system with more than 125 undergraduate degrees and 320 graduate and professional programs.