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-starred 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.