Palmer was born in Harvey, Illinois and grew up in Robbins, Illinois. She began singing as a five-year-old in her church choir. She auditioned for a stage production of The Lion King at the age of nine. Although she did not win the role, she fell in love with the process and business. Her family moved to Los Angeles in 2003 so Palmer could pursue a screen career.

Palmer made her acting debut in the movie Barbershop 2: Back In Business as Gina's niece, and between 2004 and 2006 she appeared in episodes of several television series, including Cold Case, Strong Medicine, ER, Law & Order: Special Victims Unit, House of Payne, and was subsequently cast in two films released in 2006: playing a supporting part in Madea's Family Reunion and starring as the lead character, Akeelah Anderson, a young girl from South Los Angeles who attempts to win a spelling bee, in Akeelah and the Bee. This film was released on April 28, 2006, and Palmer's performance has received several positive notices, including film critic Roger Ebert's comment that she deserved consideration for an Academy Award for Best Actress.

Palmer is also pursuing a career in singing. She participated in the 2003 American Juniors, an American Idol spin-off, but the show was canceled before Keke's was set to appear. Palmer signed a record deal with Atlantic Records. Her debut single, "All My Girlz," is featured on the Akeelah and the Bee soundtrack. On November 18, 2006, she performed at the Home Depot Center in Carson, California for VH1's Save the Music Battle of the High School Marching Bands, marking her first ever stadium performance in front of thousands of people. In addition, as part of her contract with Disney, Palmer sang the songs "It's My Turn Now" and "Jumpin'" featured in the DCOM Jump In!, in which she also stars as Mary, love interest to Corbin Bleu She recently finished her new song "Keep it movin." Palmer sings the debut single "Come On Come On" from the upcoming Hello Kitty album "Hello World". Her debut album So Uncool was released on September 18, 2007, on Atlantic Records.

She recently appeared in the video for Ludacris' and Mary J. Blige's' "Runaway Love" as Erica. In 2007, she was nominated for the NAACP Image Award for Outstanding Actress in a movie (for Akeelah and the Bee), and is one of the youngest actresses to be nominated for that award. Keke attended the 2007 Stellar Awards which were shown on BET. In 2006, Palmer recorded a song called “Tonight” for the 2006–2007 production Night at the Museum. Palmer's song is featured as the opening song on the end credits. She also guest-starred as the bully in the premiere episode of Tyler Perry's House of Payne and as a famous celebrity named CeCe on the Nickelodeon series Just Jordan.

Palmer is scheduled to play legendary rap emcee Roxanne Shanté in The Vapors, a film about the formation and rise of the Juice Crew. Palmer was given her own television series on Nickelodeon titled True Jackson, VP which she stars as 15 year old Vice President of a fashion company. The series premiered on November 8, following the iCarly TV Movie "iGo to Japan." She recently signed a record deal with Sony Records.