In 1994, Taran Killam made his first film appearance as an adolescent in Naked Gun 33⅓: The Final Insult.

Killam joined the cast of MADtv as a feature player during the 2001-2002 season. Joining the MADtv cast at age 19, Killam was the youngest cast member to ever join the long-running sketch program. He was also a regular cast member on the third and fourth seasons of Nick Cannon's Wild 'N Out. Nobody's Watching never aired on network TV, however the show was leaked and webisodes continued until June 2007 on YouTube.

After MADtv, Killam appeared on TV shows such as How I Met Your Mother, Jake in Progress, Still Standing, Boston Public, The Amanda Show, Drake & Josh, Do Over, Roswell and Judging Amy. He had also appeared on Scrubs and Scrubs: Interns as Jimmy (The Overly Touchy Orderly).

Killam co-starred in the 2004 Disney Channel Original Movie, Stuck in the Suburbs, with Danielle Panabaker, Sophie Hudgens and Brenda Song. He also sang a number of songs on the soundtrack. Other film credits include roles in Just Married, Big Fat Liar, Anderson's Cross, and My Best Friend's Girl.

Killam appeared as a contestant on the episode of The Price Is Right which aired on December 7, 2006; the episode was re-aired on July 19, 2007.

Killam is a member of the Los Angeles-based improvisational and sketch comedy troupe, The Groundlings.

On September 25, 2010, Killam joined the cast of Saturday Night Live for the 36th season, making Killam the second SNL cast member who was previously a cast member on its former rival sketch show MADtv (the first being Jeff Richards) and the second cast member (after Kenan Thompson) to be featured on children's shows that have aired on the cable channel Nickelodeon (Thompson was on the sketch show All That and the sitcom Kenan and Kel while Killam appeared on The Amanda Show and Drake and Josh).