Following Oxford, Wilson served from 1956 to 1958 in the U.S. Air Force as an intelligence officer with the Strategic Air Command.
In 1958, Wilson returned to Michigan State to serve as assistant to the vice president of academic affairs. From 1959 to 1963, he was the assistant to the president at the State University of New York. He then returned to Michigan State to help lead the Honors College, first as the assistant director and then as program director in 1965. In 1967, he became director of undergraduate education and assistant provost. From 1965 to 1969, Wilson also taught Shakespeare and Elizabethan literature at Michigan State as an assistant professor of English.
In 1968, Wilson became president of Wells College, Aurora, N.Y. He served there until 1975, when he joined Virginia Tech as executive vice president and its first provost.
During his tenure, W&L became coeducational, doubled its endowment, renovated its 15 fraternities in what came to be known as the Fraternity Renaissance, and opened the Lenfest Center for the Performing Arts.
He spent the fall term of 1988-1989 on administrative leave at Exeter College, Oxford University.
Wilson's term closed with the implementation of the then-largest capital campaign in W&L history, "On the Shoulders of Giants," which raised $147 million between 1990 and 1995. The funds allowed the construction of the Watson Pavilion and the Duchossois Tennis Center and the transformation of Parmly and Howe Halls into the Science Center. The bulk of the money supported student aid and expanded computer support and academic programs.
In 2006, the John and Anne Wilson Hall opened at Washington and Lee. Next door to the Lenfest Center, it is headquarters for the University's departments of art and music. Longtime W&L benefactors Marguerite and Gerry Lenfest ‘53, ‘55L gave a major gift to name the building in honor of President Emeritus and Mrs. Wilson.