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She began acting in film and on television during the early 1990s. She made her debut on television in 1993 on an episode of ABC legal drama Matlock and in later years appeared in TV movies, such as In the Heat of the Night: Give Me Your Life, Her Deadly Rival, Close to Danger, Any Place But Home, Nathan Dixon and Pirates of Silicon Valley. In 1996 she appeared on the CBS miniseries A Season in Purgatory based on 1993 novel with the same name by Dominick Dunne.
McBride guest starred in several television series, including American Gothic, Profiler, Walker, Texas Ranger, and Dawson's Creek.
McBride worked as a film and commercial casting director in Atlanta, Georgia from 2000 until, in 2010.
In 2007 director Frank Darabont cast McBride as the "Woman With Kids at Home" in the ensemble cast science-fiction horror film The Mist based on the 1980 novella of the same name by Stephen King.
- The Mist
- Pirates of Silicon Valley
- The Dangerous Lives of Altar Boys
- Mutant Species
- Close to Danger
- Any Place But Home
- Living Proof
- The Reconstruction of William Zero
- The Happys
- Satellite Awards in 2012 for Best Cast on The Walking Dead (TV Series)
- Saturn Award for Best Supporting Actress on Television. (2014 and 2015)
- Emmy Award for Best Supporting Actress in a Drama Series (2015)
- (Nominated) Critics' Choice Television Award for Best Supporting Actress in a Drama Series.
- Melissa McBride is the only co-star to be promoted to the main cast.
- McBride is the only main billed actor on the series not to audition for the role of her character. Frank Darabont's agency had simply called her in the casting director's office, having worked with her before in The Mist, and she agreed to play the role, but believed it would be a short term gig.
- McBride's character was supposed to be killed off in Season 3, but Melissa, as well as some of her co-stars, talked the producers out of it.
- Before going into acting, McBride wanted to be a fashion designer.