Landing in Los Angeles, Duncan decided to give showbiz a try and began to audition. Despite moments of despair, he stuck it out and began to land small roles in commercials (as a drill sergeant in a beer advertisement), on TV (e.g., playing a bouncer on Fox's "Married... With Children") and in films (i.e., cast again as bouncers in "Bulworth" and "A Night at the Roxbury", both 1998). Duncan landed a break when the actor originally tapped to play the appropriately named 'Bear' in "Armageddon" (1998) was not available and he was cast. In a go-for-broke move, just before his audition with producer Jerry Bruckheimer and director Michael Bay, he poured a bottle of water over his head and then read for them; he was cast in the part.

During the filming of "Armageddon,” he was befriended by Bruce Willis and it was because of Willis that Duncan was cast in his breakthrough role. Having read the Stephen King novel and knowing that Darabont was casting "The Green Mile", Willis called the director and told him, "I've found your John Coffey." Duncan's auditions and screen test eventually sealed the deal and he went on to deliver a memorable portrait of a childlike man with paranormal abilities who finds himself on death row. Amidst an ensemble cast that included such strong personalities as Tom Hanks, David Morse, Sam Rockwell and James Cromwell, Duncan more than held his own, sparking the inevitable Oscar buzz which indeed came to pass—Duncan made the short list as one of the five nominees for Best Supporting Actor of 1999.

Meanwhile, he and Willis continued their professional relationship as co-stars of the crime comedy "The Whole Nine Yards" (2000). In 2002, Duncan was cast in "The Scorpion King", a box-office smash directed by Chuck Russell and starring The Rock. The massive actor next appeared as the villainous mob boss Wilson 'The Kingpin' Fisk in the 2003 adaptation of the Marvel Comics superhero "Daredevil" opposite Ben Affleck and Jennifer Garner. Duncan stepped behind a microphone and offered his distinctive voice for a couple of projects: he supplied the voices of Tug in Disney’s “Brother Bear” (2003) and Clydesdale in the combination live-action and animated family comedy “Racing Stripes” (2005). Next was another outing based on graphic novels: Clarke appeared as the mysterious one-eyed enforcer Manute in director Robert Rodriguez and writer-artist Frank Miller's visually arresting adaptation of Miller's crime noir comic book series "Sin City" (2005).

After a scene-stealing, albeit short, appearance in Michael Bay’s dreadful sci-fi actioner, “The Island” (2005), starring Ewan McGregor and Scarlett Johansson as two harvested beings trying to escape a utopian facility that genetically engineers humans for organ parts, Duncan costarred in “Talladega Nights: The Ballad of Ricky Bobby” (2006), playing the pit crew chief for a go-for-broke race car driver (Will Ferrell) hell-bent on finishing first or not finishing at all. Duncan and Ferrell had one hilarious hospital scene where the two tearfully scream at each other. “Talladega Nights” opened to strong reviews, some claiming that—though flawed—it was the best comedy of the summer. He next costarred in “School for Scoundrels” (2006), playing the assistant of an unorthodox and overly-competitive life coach (Billy Bob Thornton) who runs a confidence building class attended by a meter maid (Jon Heder) plagued by anxiety and low self-esteem.