St. Francis College was established in 1939 on the mouth of the Saco River in Biddeford, Maine, as College Séraphique, a high school and junior college for young Franco-American men. In 1953, the Franciscan Order transformed the institution into a four-year liberal arts college, St. Francis College. St. Francis underwent many changes from 1968-1974 as the Franciscans in Montreal transferred ownership to a board of lay people. The College redefined its mission around programs in the biological sciences, human services, and business administration. Partnership with the New England Foundation for Osteopathic Medicine led to the founding of the New England College of Osteopathic Medicine on the campus in 1978, and the creation of the University of New England as one institution.

A momentous achievement of St. Francis College was a series of symposia held in the 1960's addressing contemporary issues. These included "The Christian in the Modern World," in response to Vatican II, and "The Negro and the Quest for Identity," a symposium that brought to St. Francis many of the nation's civil rights leaders, including Dr. Martin Luther King, Jr., Roy Wilkins, Stokely Carmichael, and Dorothy Day. That visit is commemorated in an exhibit in UNE's Leonard Hall.​