Vicki Lewis was born in Cincinnati, Ohio and graduated from Anderson High School in 1978. She wanted to pursue a career in dancing, but attended the University of Cincinnati instead,where she studied musical theatre.

She received her diploma from the Cincinnati College Conservatory of Music and moved to New York. She proceeded to work in various on and off Broadway shows for ten years. She appeared in The Crucible, Damn Yankees, and I Can Get it For You Wholesale. Director James L. Brooks saw one of her performances and signed her for his film, I'll Do Anything in 1993. This led to several small roles on tv shows such as Seinfeld, Home Improvement, and Caroline in the City.

In 1995, she auditioned for the part of Beth in NewsRadio. Mr. Brooks, who had already had a working relationship with Lewis, was directing the pilot for the show and helped her win the part over more than thirty other actresses. That, and Paul Simms, writer and creator of NewsRadio, was impressed with her line readings, saying that she had read it differently than those auditioning before her. She played this role until the shows end in 1999.

Then in 2001, she returned to television in the short-lived NBC television series Three Sisters. She has appeared in such movies as Mousehunt, Godzilla, Pushing Tin and Out of Omaha in which she teams up with her former NewsRadio castmate Dave Foley. Lewis has also done voice work over the years, most notably as Deb/Flo in the Disney/Pixar film Finding Nemo.