As of the late 1990s, Ponzio began appearing in supporting guest roles on television series, including Dawson's Creek, One Tree Hill, Surface, Drop Dead Diva, CSI: Crime Scene Investigation, The Gates, NCIS, The Following and Banshee. She also appeared in films The Greenskeeper (2002), Road Trip: Beer Pong (2009), Life as We Know It (2010) and Upside (2010).[citation needed]
Ponzio is known for her recurring roles as Angie on the Lifetime Television drama series Army Wives (2007–2009), and as Melissa McCall in the MTV teen drama Teen Wolf (2011–2017). In 2013, she had a recurring role as Karen in the AMC drama series The Walking Dead.
In September 2021, it was announced that a reunion film for 2011 Teen Wolf television series had been ordered by Paramount+, with Jeff Davis returning as a screenwriter and executive producer for the film. The majority of the original cast members, including Ponzio herself, will reprise their roles, The film was released on January 26, 2023.

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