The 1990s brought D'Onofrio supporting roles in high-profile ensemble pictures: as witness Bill Newman in Oliver Stone's controversial "JFK" (1991), a role he reprised in a bit part for Spike Lee's "Malcolm X" (1992), and as Orson Welles in Tim Burton's affectionate biopic "Ed Wood" (1994). He was most memorable in Robert Altman's winsome industry satire "The Player" (1993). As David Kahane, the beefy, thwarted lover of 50s foreign films and his own scripts, D'Onofrio played a victim of Hollywood and homicide in a small role that was central to the film's brilliantly snaking plot. He also turned up in slight comedies of an "ethnic" variety, playing Matt Dillon's best friend in "Mr. Wonderful" (1993) and Joseph in Nancy Savoca's lovely "Household Saints" (1993).

D'Onofrio has occasionally tackled starring roles like pulp writer and "Conan" creator Robert E. Howard in "The Whole Wide World" (1996, which he also produced) and habitual loser Philip in "The Winner" (1997), but his staple has remained character work. He provided a genuinely touching moment as Al Franken's brother in the dismal "Stuart Saves His Family" (1995) and a chilling turn rising up gun in hand, that "Full Metal Jacket" look in his eyes, for "Strange Days" (1995). His evil intergalactic insect in purloined human skin offered a formidable foe to agents Will Smith and Tommy Lee Jones in Barry Sonnenfeld's summer blockbuster "Men in Black" (1997). D'Onofrio then co-starred alongside Matthew McConaughey, Skeet Ulrich and Ethan Hawke as the real-life bank and train robbers, "The Newton Boys" for director Richard Linklater, and with Salma Hayek and Thomas Jane in the triangular romance "The Velocity of Gary (Not His Real Name)" (both 1998).

Following his turn as a former basketball champion in the 1999 Showtime remake of "That Championship Season", the actor played a time-traveling hero from the future who visits 1990s NYC in an attempt to woo and save a woman (Marisa Tomei) with whom he has fallen in love in "Happy Accidents". (The film premiered at the 2000 Sundance Film Festival but did not receive theatrical distribution until 2001). He next tackled the challenging part of real-life "yippie" and government fugitive Abbie Hoffman in the biopic "Steal This Movie" (2000). While he did not exactly resemble Hoffman, D'Onofrio captured his spirit and delivered a finely wrought performance that went overlooked when the film stumbled at the box office. He enjoyed a more commercial fate as a serial killer whose mind is penetrated by a therapist in an experimental fashion in the visually imaginative but dramatically inert "The Cell" (also 2000). While the actor remained busy with film projects (several of which wouldn't be released until 2002 like "The Salton Sea" and "Impostor"), he also accepted an offer from producer Dick Wolf to star in the second spin-off of the popular "Law & Order". Teamed with Kathryn Erbe, D'Onofrio was cast as the highly intuitive detective Robert Goren in "Law & Order: Criminal Intent" (NBC, 2001- ).