After taking some minor acting roles in 1992, including the Jonze-directed Sonic Youth music video for "100%," and a small part in Allison Anders' 1993 film Mi Vida Loca, Lee left professional skateboarding for a full-time acting career. His first major movie role was in Kevin Smith's Mallrats, which became a cult hit. This started a friendship that subsequently led to appearances in many of Smith's films, including Chasing Amy, Dogma, Jay and Silent Bob Strike Back, Clerks 2, and Cop Out. Lee won an Independent Spirit Award for his role in Chasing Amy as Banky Edwards, a comic book inker.
Lee graduated to leading man roles in Heartbreakers (with Jennifer Love Hewitt) and Stealing Harvard (with Tom Green), as well as A Guy Thing (with Julia Stiles). He has had supporting roles in Vanilla Sky, Almost Famous as a rock star, Dreamcatcher, Big Trouble, The Ballad of Jack and Rose, and Mumford, as well as a minor role in Enemy of the State. Lee also voiced the supervillain Syndrome in the animated movie The Incredibles and its DVD bonus video Jack-Jack Attack. Lee reprised the role as a "robot copy" of Syndrome in the 2006 Disney on Ice play Disney Presents Pixar's The Incredibles in a Magic Kingdom Adventure. He is also the voice of Underdog in Underdog and plays David "Dave" Seville in the films Alvin and the Chipmunks, Alvin and the Chipmunks: The Squeakquel and Alvin and the Chipmunks: Chipwrecked''
In 2005, Lee was offered the lead role in the NBC sitcom My Name Is Earl. According to interviews on the first-season DVD, he passed on the series twice before finally agreeing to read for the pilot. In the series, Lee stars as Earl Hickey, a petty thief who discovers karma and sets out to put right all his past wrongs. Lee received two Golden Globe nominations for Best Performance by an Actor in a Television Series – Musical or Comedy in 2006 and 2007, as well as a nomination for the Screen Actors Guild Award for Outstanding Performance by a Male Actor in a Comedy Series in 2006. After four seasons of My Name is Earl NBC cancelled the series.
On June 22, 2010, the new TNT series Memphis Beat premiered. Lee stars with Alfre Woodard and plays Dwight Hendricks, a character who works as a police officer and moonlights as a blues singer. In October 2011, it was announced the series was not renewed for a third season.
Lee also guest-starred on an episode of Fox's Raising Hope, a show created by My Name is Earl producer and creator Greg Garcia.
Beginning in October 2011, Lee became a recurring guest star in the new NBC comedy Up All Night.
2000 Almost Famous Jeff Bebe
2001 Heartbreakers Jack Withrowe
Jay and Silent Bob Strike Back Brodie Bruce / Banky Edwards
Vanilla Sky Brian Shelby
2002 Big Trouble Puggy
Stoked: The Rise and Fall of Gator Documentary
Stealing Harvard John Plummer
2003 A Guy Thing Paul
I Love Your Work Larry Hortense
2004 Oh, What a Lovely Tea Party Documentary
Jersey Girl PR Exec #1
The Incredibles Syndrome / Buddy Pine ("IncrediBoy") (voice)
2005 The Ballad of Jack and Rose Gray
Drop Dead Sexy Frank
2005–2009 My Name Is Earl Earl Hickey TV Series: 96 Episodes
Also Producer for 50 Episodes
2006 Clerks II Lance Dowds
Rising Son: The Legend of Christian Hosoi Documentary
Monster House Bones Voice
2007 Underdog Underdog (Shoeshine) Voice
The Man Who Souled the World Documentary
Alvin and the Chipmunks David "Dave" Seville
2008 Celebrity Family Feud
2009 Alvin and the Chipmunks: The Squeakquel David "Dave" Seville
2010 Cop Out Roy
Raising Hope Smokey Floyd TV, Guest Star
2010-2011 Memphis Beat Dwight Hendricks TV series: 20 episodes
2011 Noah's Ark: The New Beginning Japheth
The Other Side Mortimer Flybait Voice
Up All Night Kevin
Alvin and the Chipmunks: Chip-Wrecked David "Dave" Seville
2012 Back in Time Henry Foster
Happy Holidays, Katherine Sloane