O'Kelley began her acting career in commercials. In the 1990s, she founded a resource center for aspiring actors in Chicago that provided workshops, career consultations and seminars. As of the late 1990s, she began her career on television, including guest-starring roles on Frasier, Suddenly Susan, Everybody Loves Raymond, Two and a Half Men, CSI: Crime Scene Investigation, Back to You, Malcolm in the Middle and starring roles in short-lived series Emeril and That Was Then. She also had a recurring role in The WB family drama series Gilmore Girls, as Nicole Leahy from 2003 to 2004.
O'Kelley is best known for her portrayal of Marly Ehrhardt on the CBS sitcom The New Adventures of Old Christine, opposite Julia Louis-Dreyfus, from 2006 to 2010. In 2009, she also starred and executive produced the independent film Weather Girl. She later starred in two television pilots, and from 2011 to 2013 had a recurring role as Camille Boykewich in the ABC Family teen drama series, The Secret Life of the American Teenager. In 2013, O'Kelley starred in the Lifetime movie Missing at 17, and in next year was cast for second season of Lifetime comedy-drama series, Devious Maids, as Tanya Taseltof.
