She began her standup comedy career in 1987 when she entered a Washington D.C.-area talent competition. Although she lost, she discovered a passion for comedy. She continued to hone her talents at local venues while working as a procurement officer at the National Security Agency (NSA). In 1992, she left the NSA and moved to New York. Her first big break came when opening for Chris Rock at Caroline`s Comedy Club. In 1997, she joined the writing team on The Chris Rock Show. The writing team was nominated for four Emmys, one of which they won in 1999. Since that time, she has appeared in such films as Pootie Tang and on TV shows such as Curb Your Enthusiasm. In 2003, she starred in her own short-lived Fox network sitcom, Wanda at Large. The same year, Sykes appeared in an hour-long Comedy Central special, Tongue Untied. That network also ranked her #70 on its list of the 100 greatest all-time standups. She served as a correspondent for HBO`s Inside the NFL, hosted Comedy Central`s popular show Premium Blend, and voices a recurring character named Gladys on Comedy Central`s puppet show Crank Yankers. She had a short-lived show on Comedy Central called Wanda Does It, where she tries out various careers. She frequently winds up choosing what career she will try out after scolding someone in an over-the-top fashion who does the particular job.

In addition to her film and television work, she is also an author. She wrote Yeah, I Said It, a book of humorous observations on various topics, published in September 2004.

In 2006, she landed a recurring role on the sitcom The New Adventures of Old Christine; she became a series regular in the second season. She also provided voices for the 2006 films Over the Hedge, Barnyard and Brother Bear 2. She had a part in My Super Ex-Girlfriend and after playing in Evan Almighty, the sequel to the Jim Carrey hit Bruce Almighty, holds a bit part in License to Wed. Sykes` first HBO Comedy Special, titled Wanda Sykes: Sick & Tired, premiered at 10:00 PM EST on October 14th, 2006. Her voice can be heard narrating the most recent Applebee`s commercials as the talking apple along with her infamous "Get it together, baby" ending.