Keys first appeared on television in 1985, where she and a group of other girls played the parts of Rudy Huxtable's sleepover guests in an episode of The Cosby Show called "Slumber Party". During the early 2000s, Keys made small cameos in such television series as Charmed and American Dreams. In October 2006, she played the voice of Mommy Martian in the "Mission to Mars" episode of the children's television series The Backyardigans, in which she sang an original song, "Almost Everything Is Boinga Here". Keys guest starred as herself in the "One Man Is an Island" episode of the drama series Cane.

Keys made her film debut in early 2007 in the crime film Smokin' Aces, co-starring as an assassin named Georgia Sykes opposite Ben Affleck, Ray Liotta, Common, Andy García, Taraji P. Henson, Jeremy Piven and Ryan Reynolds. Keys received much praise from her co-stars in the film; Reynolds said that Keys was "so natural" and that she would "blow everybody away". In the same year, Keys earned further praise for her second film, The Nanny Diaries, based on the 2002 novel of the same name by Emma McLaughlin and Nicola Kraus. She co-stars alongside Scarlett Johansson, Chris Evans, Paul Giamatti and Laura Linney. She also starred in The Secret Life of Bees, a film adaptation of Sue Monk Kidd's acclaimed 2003 bestseller novel of the same name alongside Jennifer Hudson and Queen Latifah, released on October 17, 2008 via Fox Searchlight.

Keys and manager Jeff Robinson signed a film production deal to develop live-action and animated projects with Disney. Their first film will be a remake of the 1958 comedy Bell, Book and Candle and will star Keys as a witch who casts a love spell to lure a rival's fiancé. Keys and Robinson also formed a television production company called Big Pita. Their first project will be a UPN television series inspired by Keys' experiences as a biracial child growing up in New York. Keys will be an executive producer of the series and has received a script commitment from the network. Keys and Robinson will develop live-action and animated projects from their company, Big Pita and Little Pita, with Keys as producer, thespian, banner spearheading soundtrack and music supervision.

Keys is expected to play a 1940s biracial piano child prodigy, Philippa Schuyler, in an upcoming film entitled Compositions in Black and White. It is based on a 1995 biographical book of the same name by Kathryn Talalay. "The challenge, in order to actually be able to play classical piano as a woman of mixed race, was by far more than I could ever imagine", Keys said. "That's what intrigued me about that role". The biopic will tell the difficult tale of Schuyler's controversial career, love-hate relationship with her mother, and the black community, her second career as a writer, and her eventual death in a helicopter accident. "Her story is very deep, even up to the point where the relationship between her and her mother gets very strained and she chooses to go to Europe and pass as a Spanish woman in order to be able to play, in order to be able to live a more normal life", Keys said, adding that she and Halle Berry hoped to start shooting in early 2008. "As of right now, we're still in the first, second draft of the script", she said. "So a little bit of time—at least a year".

• The Secret Life of Bees (2008) .... June Boatwright
• The Nanny Diaries (2007) .... Lynette
• Smokin' Aces (2006) .... Georgia Sykes
  ... aka Mi$e à prix (France)
• "The Backyardigans" .... Boinga's Mom (1 episode, 2006)
       - Mission to Mars (2006) TV episode .... Boinga's Mom
• "American Dreams" .... Fontella Bass (1 episode, 2003)
  ... aka Our Generation (Australia) (USA: working title)
       - Rescue Me (2003) TV episode .... Fontella Bass
• "Charmed" .... P3 VIP Patron (1 episode, 2001)
       - Size Matters (2001) TV episode (uncredited) .... P3 VIP Patron
  
• "The Cosby Show" .... Maria (1 episode, 1985)
       - Slumber Party (1985) TV episode (as Alicia Cook) .... Maria