Fussell was drafted into the Army in 1943, at age 19. In October 1944 he landed in France, as part of the 103rd Infantry Division. On November 11th, he experienced his first night on the front lines. He was wounded while fighting in France as a second lieutenant. Fussell suffered from depression and rage for years following his military service. In his 1996 autobiography he associated this condition with the dehumanization of his military service and his anger at the way the United States government and popular culture romanticized warfare. Since the 1980s Fussell has been an outspoken critic of the glorification of military service and warfare. An early influence was H. L. Mencken, but he shed Mencken as a mentor, calling him "deficient in the tragic sense", after his wartime experience.
He spent his undergraduate years at Pomona College, and earned a Ph. D. at Harvard University. He has taught at Connecticut College, Rutgers University, the University of Heidelberg, King's College London, and the University of Pennsylvania. He retired from teaching in the mid-1990s.
Fussell's 1975 literary study The Great War and Modern Memory (1975) won the National Book Award for Arts and Letters, the National Book Critics Circle Award for Criticism, and the Ralph Waldo Emerson Award of Phi Beta Kappa. Military historian John Keegan calls it a "simply superb book". Lynne Hanley, however, offers a strong critique of the The Great War and Modern Memory in her 1991 text, Writing War: Fiction, Gender & Memory.
Fussell was one of several veterans interviewed in the Ken Burns documentary The War in 2007.
His first wife, Betty Fussell, a food writer and biographer, whom he met at Pomona College, has written a memoir, My Kitchen Wars (1999), that discusses their more than 30 years of marriage in highly negative terms, including allegations that Fussell had adulterous affairs with both men and women.
Fussell now lives in Philadelphia, with his second wife, Harriette Behringer. They met in 1983, when she sent him a postcard introducing herself, after reading an article about him. Now retired, she worked in journalism and public relations. His son, Samuel Fussell, is the author of Muscle: Confessions of an Unlikely Bodybuilder (1991). His brother Edwin Sill Fussell was also a professor of English literature.