"[5] She has appeared in numerous films, including Changing Lanes (2002) with Ben Affleck, Maid in Manhattan (2002) with Jennifer Lopez, and Garden State (2004) with Zach Braff and Natalie Portman.

[8] During this time she acted in Trust the Man (2006) with Julianne Moore, and Everybody's Fine (2009) with Robert De Niro, Kate Beckinsale, Drew Barrymore, and Sam Rockwell.

In 2010, she starred as the Stage Manager in the film Morning Glory opposite Harrison Ford, Diane Keaton, and Rachel McAdams.

She played the role of "Hattie" in the 2011 revival of Follies,[17] and received a 2012 Tony Award nomination, Featured Actress in a Musical for her performance.

In 2015, she starred as Rose Offer on the NBC limited series American Odyssey opposite Anna Friel and Peter Facinelli.

[30] In 2019, she appeared as the housekeeper Hannah in Greta Gerwig's critically acclaimed and Oscar-nominated film adaptation of Little Women starring Saoirse Ronan, Emma Watson, Florence Pugh, Eliza Scanlen, Laura Dern, Timothée Chalamet, and Meryl Streep.

[31] In April 2019, Houdyshell returned to Broadway as the Earl of Gloucester in the Sam Gold directed production of King Lear, with Glenda Jackson in the title role.

[35] That same year she acted in the psychological drama film Causeway directed by Lila Neugebauer and starring Jennifer Lawrence and Brian Tyree Henry.

She returned to Broadway in the revival of Anton Chekov Uncle Vanya at Vivian Beaumont Theater starring Steve Carell, Allison Pill, William Jackson Harper, and Alfred Molina.