After earning his drama degree in 1979, Karn moved to New York City. After less than one week, he was hired to do a commercial for Michelob beer that was featured during the 1980 Super Bowl. When he joined the Screen Actors Guild, he was informed there was already a Richard Wilson, so he dropped his last name.

In 1989, his wife Tudi convinced him that they should move to Los Angeles. He found a place for them to live by managing an apartment complex, and catered events at a Jewish synagogue on the side. After receiving a traffic citation, Karn attended a traffic school and sat beside an agent who told him about casting for the new television show called Home Improvement. The role of Al Borland had already been given to Stephen Tobolowsky, but when taping was scheduled, Tobolowsky was busy with another movie and the role had to be recast. Karn was a guest star in the pilot episode but became a regular cast member when the show was picked up by the network.

Karn did commercials for Orchard Supply Hardware in the 1990s.

In 2002, Karn also made an appearance in The Strokes' music video for "Someday", which featured segments of the band on a fictional showing of Family Feud against the band Guided by Voices.

On October 6, 2008, Karn replaced Patrick Duffy as host of Game Show Network's Bingo America. Karn was also a substitute host on GSN Radio.