Lewis was born and raised in Cincinnati, Ohio, the daughter of Marlene, a nursing administrator, and Jim Lewis, an air traffic supervisor. She has a sister, Denise. Lewis graduated from Anderson High School in Cincinnati in 1978. She studied musical theater at the University of Cincinnati – College-Conservatory of Music. After receiving her diploma she moved to New York City. She proceeded to work in various on and off-Broadway shows.
Lewis was in a long-term relationship with Nick Nolte. The two met during the filming of I'll Do Anything. She is married to sound designer Philip G. Allen.
Lewis's film appearances include roles in Finding Nemo, Finding Dory, Mouse Hunt, Godzilla, Pushing Tin, 2007's California Dreaming with NewsRadio co-star Dave Foley, and 2010's Den Brother. On television, Lewis starred for 5 seasons on the NBC sitcom NewsRadio, followed by Three Sisters and the WB animated comedy Mission Hill. She made guest appearances on Seinfeld (in the episodes "The Secretary" and "The Race") and Murphy Brown. In a recurring role on Home Improvement, she played Maureen Binford, producer of the show-within-a-show Tool Time. On How I Met Your Mother, she had the recurring role of Lily Aldrin's doctor, "Dr. Sonya".

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