Keegan-Michael Key and his former MADtv castmate Jordan Peele star in their own Comedy Central sketch series Key & Peele, which began airing in 2012, and has run for four seasons.

In March 2015, it was announced that Key will reprise his role as Mr. Garvey in a feature length film based on the character portrayed in sketches on the show, while Peele will portray a rival teacher.

Key joined the cast of MADtv midway into the ninth season. He and Jordan Peele were cast against each other so that FOX could pick one black cast member, but both ended up being picked after demonstrating great comedic chemistry.

Key played many characters on the show. One of his most famous characters is "Coach Hines", a high school sports coach who frequently disrupts and threatens students and faculty members. On the penultimate episode of MADtv, Hines revealed that he is the long-lost heir to the Heinz Ketchup company and only became a Catholic school coach to help delinquent teenagers like Yamanashi. During seasons 9 and 10, Key appeared as "Dr. Funkenstein" in blaxploitation parodies, with Jordan Peele playing the monster.

Key also portrayed various guests on Real **********ing Talk like the strong African Rollo Johnson and blind victim Stevie Wonder Washington. He often goes "backstage" as Eugene Struthers, an always-ecstatic water- or flower-delivery man who accosts celebrities. There is also "Jovan Muskatelle", a shirtless man with a jheri curl and a shower cap. He interrupts live news broadcasts by a reporter (always played by Ike Barinholtz), annoying him with rapid fire accounts of events that have happened frequently exclaiming "It was crazy as hell!"

Celebrities that Key impersonated on the show include Ludacris, Snoop Dogg, Matthew Lillard, Bill Cosby, Al Roker, Terrell Owens, Tyler Perry, Robin Antin, Keith Richards, Eddie Murphy (as his character James "Thunder" Early from the movie Dreamgirls), Sherman Hemsley (as his character George Jefferson on The Jeffersons), Charles Barkley, Sendhil Ramamurthy (as Mohinder Suresh), Tyson Beckford, Seal (originally played by Jordan Peele until Peele left the show at the end of season 13), Sidney Poitier, Lionel Richie, Barack Obama, and Kobe Bryant.

He also played female celebrities, including Phylicia Rashād, and Eva Longoria (as Gabrielle Solis on a "Desperate Housewives" parody).