Born in Brooklyn, NY, on June 30, 1959, D'Onofrio was raised in the diverse locales of Hawaii, Colorado, and Miami's Hialeah section. His career as an actor began on the stage, with study under Sonia Moore of New York's American Stanislavski Theatre and Sharon Chatten at the Actors Studio. D'Onofrio's early years in the theater were filled with an obligatory helping of obscurity and miniscule paychecks (so miniscule that he worked for a time as a bouncer to help pay the bills). His fortunes began to shift in 1984, when he joined the American Stanislavski Theatre as a performer. There, he appeared in such well-regarded productions as Of Mice and Men and David Mamet's Sexual Perversity in Chicago, and also made his Broadway debut in Open Admissions.

D'Onofrio debuted onscreen in the straight-to-oblivion 1983 comedy The First Turn-On!, but it was not until his haunting portrayal of Pvt. Pyle (a role for which the actor gained 70 pounds) four years later in Stanley Kubrick's Full Metal Jacket that he earned much-deserved notice for his work. Defying easy categorization, D'Onofrio next appeared in the romantic comedy Mystic Pizza (1988), slimming down to his normal weight and giving a convincing portrayal as Lily Taylor's lovestruck boyfriend.

Having thus given audiences a glimpse of his remarkable versatility, D'Onofrio spent the next few years making his presence felt in such films as JFK (1991), in which he played assassination witness Bill Newman; The Player (1992), which cast him in the pivotal role of ill-fated screenwriter David Kahane; and Nancy Savoca's Household Saints (1993), which, through a particularly odd feat of casting, had him playing the father of Lily Taylor. Although D'Onofrio worked at a prolific pace, it was not until he portrayed Conan the Barbarian author Robert E. Howard in the 1996 The Whole Wide World that he really had his screen breakthrough. A low-key romantic drama about the relationship between Howard and a schoolteacher (Renee Zellweger), the film allowed D'Onofrio to take center stage, rather than lend support to better-known co-stars. Critics roundly applauded his performance, but although the actor kept working steadily, he was by no means a Hollywood fixture. Eschewing the limelight, he turned in particularly memorable performances in Feeling Minnesota (1996) as Cameron Diaz's cuckolded fiancé and in the 1997 blockbuster Men in Black, which cast him as the film's resident bad guy.