Missi Pyle made her screen debut in the 1997 James L. Brooks-directed American romantic comedy-drama film ‘As Good as It Gets’ where she played the role of a cafe waitress. The film received mostly positive reviews from critics and was a major financial success, grossing over $314.1 million on a $50 million budget. In 1999, she played the role of ‘Laliari’ in the American science fiction comedy film ‘Galaxy Quest’ directed by Dean Parisot. While the film received a positive response from critics, it was a moderate success at the box office. She next starred in films like ‘Josie and the Pussycats’ (2001), ‘Home Alone 4: Taking Back the House’ (2002), ‘Bringing Down the House’ (2003), ‘Big Fish’ (2003), ‘Along Came Polly’ (2004), ‘50 First Dates’ (2004), ‘DodgeBall: A True Underdog Story’ (2004), ‘Anchorman: The Legend of Ron Burgundy’ (2004), and ‘The Civilization of Maxwell Bright’ (2005). In 2005, she portrayed ‘Mrs. Beauregarde’ in the musical fantasy film ‘Charlie and the Chocolate Factory’ directed by Tim Burton. The film saw positive reviews upon release and grossed over $475 million on a budget of $150 million. She continued to appear in films like ‘Just My Luck’ (2006), ‘Stormbreaker’ (2006), ‘Live!’ (2007), ‘Feast of Love’ (2007), and ‘Pretty Ugly People’ (2008).
She starred as ‘Raylene’ in the 2008 American buddy stoner comedy film ‘Harold & Kumar Escape from Guantanamo Bay’ directed by Jon Hurwitz and Hayden Schlossberg. Even though the film opened to a mixed critical reception, it managed to emerge as a commercial success. Pyle was next seen in films like ‘Still Waiting…’ (2009), ‘Taking Chances’ (2009), ‘Barry Munday’ (2010), ‘A Cinderella Story: Once Upon a Song’ (2011), ‘My Uncle Rafael’ (2012), ‘Percy Jackson: Sea of Monsters’ (2013), ‘A Haunted House 2’ (2014), ‘Just Before I Go’ (2014), ‘Gone Girl’ (2014), ‘Uncle Nick’ (2015), ‘Captain Fantastic’ (2016), ‘Pandemic’ (2016), ‘Deidra & Laney Rob a Train’ (2017), ‘Jumanji: Welcome to the Jungle’ (2017), ‘Traffik’ (2018), and ‘Ma’ (2019). She was last seen in the American musical comedy-drama television series ‘The Big Leap’ in 2021.