Harrelson demonstrated some big-screen credibility as the romantic rival of Michael J Fox in the comedy "Doc Hollywood" (1991), though the role of a small-town insurance salesman was not much of a stretch from his weekly job as a naive bartender. Harrelson's film career received a major boost from his first lead in a major motion picture, Ron Shelton's "White Men Can't Jump" (1992), which proved one of the surprise box-office hits of the year and a suitable showcase for his relaxed, offhand and self-aware charm. Well-paired with Snipes, he proved all-too-credible as a basketball hustler who masquerades as a goofball. Trying to shake off the shade of his TV alter ego, Harrelson enjoyed an even greater popular (if not critical) success as the venal but jealous yuppie husband of Demi Moore in the fanciful romantic drama "Indecent Proposal" (1993) but fared less well opposite Kiefer Sutherland as a country boy in the big city in the standardized "buddy" comedy-actioner "The Cowboy Way" (1994).

Perceiving a heretofore unexplored violence in the generally amiable actor, bombastic auteur Oliver Stone cast Harrelson against type in his "Natural Born Killers" (1994). As Mickey Knox, half of a murdering couple, the actor's still potent "nice guy" image may have helped some audiences to better tolerate his character's brutal misdeeds. Others just could not get past the pre-existing persona. The film itself did healthy business and garnered wildly mixed reviews. "Money Train" (1995) was an uninspired (an uninspiring) reuniting with Snipes as they played foster brothers and transit cops with larceny on their minds. A presumably copycat crime in NYC stirred up some controversy (Senator Bob Dole called for a boycott of the movie), but business was disappointing. As he told the Daily News (January 3, 1999), it remains "probably the least favorite of any movie I've ever done", one which convinced him never again to take on a project simply for the money.

Working steadily, the sometimes controversial Harrelson (due to his once libertine lifestyle, left-leaning politics, penchant for New Age therapies and sometimes erratic on-set behavior) turned up in three diverse high-profile features in 1996: as a one-armed former bowling hustler in "Kingpin" (think Martin Scorsese's "The Color of Money" re-imagined as an extremely crude bowling comedy); as an initially unsympathetic physician taken hostage by an ailing renegade Native American teen in Michael Cimino's "Sunchaser"; and controversial pornographer Larry Flynt in Oliver Stone's production of Milos Forman's biopic "The People vs. Larry Flynt". The first two were very forgettable, and the third, a powerful endorsement of the First Amendment, did not play well across the country, despite critical raves, most likely because people frowned on the notion of Flynt as a hero. Although Courtney Love's portrayal of Flynt's wife Althea was the true revelation of the film, the increasingly versatile Harrelson was perfect as the mercurial "sleazebag,” and his Oscar-nominated performance further distanced him from Woody Boyd.

Harrelson was flamboyant in the relatively small role of a spaced-out US TV journalist in "Welcome to Sarajevo", gaining layers of depth as the picture progressed, notably in scenes following his return from discovering Serbian concentration camps, and was suitably heroic as "good old shoe" Sergeant William Schumann in Barry Levinson's "Wag the Dog" (both 1997). As the star of that year's "Palmetto", however, he couldn't conjure the character missing from the screenplay but rebounded with an outstanding performance as the larger-than-life hellraiser Big Boy Matson in "The Hi-Lo Country" (1998), fleshing out the powerful life force provided by screenwriter Walon Green. In this underrated, hard-edged romance, his Big Boy personified the dying breed of rugged individualists unable to compete against the Sam Elliotts of corporate farming in the post-World War II West. After delivering a memorable cameo in Terrence Malick's "The Thin Red Line" (also 1998), he returned to his comic roots as Matthew McConaughey's rakehell brother in Ron Howard's "EDtv" (1999).

Switching gears again, Harrelson reunited with Ron Shelton to star alongside Antonio Banderas as washed-up boxers attempting to rejuvenate their careers in Las Vegas in "Play It to the Bone" (2000). Aside from a starring role in the little-seen caper comedy "Scorched" (2003), Harrelson appeared primarily in cameo or supporting roles in films such as "Anger Management" (2003) and "She Hate M (2003), instead making more news in his off-screen life as a proponent of a vegan diet, the co-owner of a San Francisco oxygen bar and as an outspoken hemp activist and environmentalist. In 2004 the actor returned to the big screen in the amiable caper film "After the Sunset" (2004), playing an obsessed FBI agent trying to goad his retired jewel thief rival (Pierce Brosnan) into one more big score. In “The Prize Winner of Defiance, Ohio” (2005), he played the bum husband of a housewife (Julianne Moore) who keeps her impoverished family afloat winning jingle contests while he drinks away the meager wages from his grueling job. After a supporting turn as a one-time local hockey hero turned big city lawyer in “North Country” (2005), Harrelson joined the ensemble cast for Robert Altman’s fictional take on Garrison Keillor’s long-running radio show, “A Prairie Home Companion” (2006), a loose anthology depicting the program on its final broadcast and populated by its usual strange cast of performing talent.