Palmer made her acting debut in the 2004 film Barbershop 2: Back in Business and rose to prominence in 2006 for her breakthrough role in Akeelah and the Bee as well as starring in Madea's Family Reunion. Palmer has also starred in films such as The Longshots (2008), Shrink (2009) and Animal (2014). In 2012, Palmer starred in four films: Joyful Noise, Winx Club: The Secret of the Lost Kingdom, Ice Age: Continental Drift, and Virgin Mary. Besides films, Palmer has also starred in the television films Knights of the South Bronx (2005), Jump In! (2007), and Rags (2012), among others. Palmer has also had numerous television roles including the lead role in Nickelodeon sitcom True Jackson, VP. Palmer earned $20,000 per episode of True Jackson, VP, which made her the fourth-highest-paid child star on television. Keke was also a series regular in the 2015 Fox horror comedy Scream Queens and the 2019 VH1 slasher Scream. In 2019, Palmer became co-host of daytime talk show Strahan, Sara and Keke on ABC alongside Sara Haines and Michael Strahan.