Meyers officially joined the cast of MADtv in 2002, as a featured performer for the eighth season. He would fill in the spot of the Spishak Spokesperson that David Herman and Pat Kilbane previously owned. Meyers was also known for his celebrity impersonations, including Anna Nicole Smith's son, Daniel, various members of *NSYNC, rapper Eminem, and actor/writer Owen Wilson.

Meyers's appearances on MADtv on FOX aired directly opposite his brother Seth's appearances on Saturday Night Live on NBC. This was referenced on a season 28 episode of Saturday Night Live in which Seth appears on Weekend Update to talk to his father and tells him to turn off MADtv.

When Topher Grace left That '70s Show, Meyers was chosen as a replacement, along with Tommy Chong, who was featured more frequently. In 2006, Meyers made an appearance in the feature film Date Movie, where he played Napoleon Dynamite and Owen Wilson's character from Wedding Crashers.

Meyers often works with Ike Barinholtz, and in 2002 they became cast members of MADtv. He had a supporting role in College Road Trip, and appeared alongside Pee-wee Herman as Firefighter, Clockey, and Conky in The Pee-wee Herman Show at Club Nokia until February 7, 2010.[citation needed]