Sandeen devoted his career to teaching, first at Knox College in Galesburg, Illinois, as an English instructor beginning in 1935. After working at the University of Iowa from 1937 to 1943, he began a lengthy association with the University of Notre Dame in Indiana. After serving as an assistant professor, then as an associate professor, he became a full professor of English in 1960 and began heading the department in 1965.
In all, his work at Notre Dame lasted fifty years; he became professor emeritus of American literature in 1976. In addition to his teaching, Sandeen wrote poetry. His verse was compiled in books such as "Antennas of Silence", "Children and Older Strangers", "Like Any Road Anywhere", and "Collected Poems, 1953-1977." He also contributed to volumes, including "Fifty Years of the American Novel" and "American Classics Reconsidered."