In 2000, Simpson made his feature film debut in the teen comedy Loser, directed by Amy Heckerling. This was followed by various roles on television, including the Stephen King miniseries Rose Red, and appearances on 24, NYPD Blue, Cold Case, and Carnivàle. Subsequent film roles included Herbie: Fully Loaded, with Lindsay Lohan (2005); Seraphim Falls, with Liam Neeson (2006); and David Fincher's Zodiac (2007).
Simpson met Actress Melanie Lynskey in 2001, when they both appeared in Rose Red. The pair became engaged in 2005 and married on April 14, 2007, in a chapel near Queenstown, New Zealand.
From 2008 to 2009, Simpson made several guest appearances as Lyle, a fictional intern, on The Late Show with David Letterman. During that time, he also appeared in episodes of CSI: Crime Scene Investigation, My Name is Earl, House, and Psych, and had supporting roles in the films The Invention of Lying, directed by Ricky Gervais (2009), and Date Night, with Steve Carell (2010).
Lynskey filed for divorce from Simpson on September 25, 2012, citing irreconcilable differences. The divorce was finalized on May 23, 2014.
In 2016, Simpson appeared in a principal role on the first season of HBO's Westworld. His character, william, is a visitor to Westworld — a Futuristic Wild West-themed amusement park populated by androids, dubbed "hosts" — who forms a protective bond with the park's oldest host, Dolores (Evan Rachel Wood). In July 2017, it was announced that Simpson would return for the show's second season.