Edwin Eliott Willoughby was born in Philadelphia, Pennsylvania on November 5, 1899, the eldest of the three children of printer Frank Faul Willoughby and his wife Annie (Smith) Willoughby. While Edwin was still a child, the family moved to New Jersey. In 1918, Willoughby entered Dickinson College in Carlisle, Pennsylvania with the class of 1922, and participated in the Student Army Air Corps as a private in the U.S. Army during the First World War. He remained at Dickinson after the war, and was active in the Belles Lettres Literary Society, the New Jersey Club, and the YMCA. He also served as associate editor of the 1922 Microcosm (the Dickinson College yearbook). After receiving his B.A. from Dickinson in 1922, Willoughby received his M.A. and Ph. D. from the University of Chicago in 1924 and 1932 respectively. While at Chicago, he was employed as a senior assistant and then reference librarian at the Newberry Library of Chicago. From 1929-1931 he was a John Simon Guggenheim Memorial Foundation fellow in London, England and studied in Europe again in the summer of 1934 on a grant from the American Council of Learned Societies.
After his return from England, Willoughby accepted the position of professor and acting director of the Library Science Department of the College of William and Mary; his tenure there lasted from 1932 until 1935. During the summer of 1934 he returned to Europe to further his studies on a grant from the American Council of Learned Societies. From 1935 until his retirement in 1958, he was Chief Bibliographer at the Folger Shakespeare Library, Washington D.C. Willoughby’s work on the history of the King James Bible as well as on Shakespeare’s printers gained him international renown and special recognition for his research. Dickinson College conferred upon him an honorary Litt. D. degree in 1940. He was a fellow of the Royal Society on Literature of Great Britain, held membership in the Bibliographical societies of London and American, American Library Association, Shakespeare Association of Great Britain, Phi Beta Kappa, American Legion, and the Grolier Club of New York. He wrote more than 300 articles and reviews and was the author of five books, as well as multiple unpublished works. Edwin E. Willoughby died in Ancora, New Jersey, on October 2, 1959, where his sister Frances L. Willoughby had been caring for him while he battled the neurological disorder that led to his death. He never married.