Her first major role was Kim Kelly in the 1999-2000 comedy-drama TV series Freaks and Geeks; Philipps appeared in all but one of the show’s 18 episodes (the exception being the episode “Chokin’ & Tokin'”). She made her film debut in the comedy The Smokers in 2000, and had various small appearances on television.

In 2001, Philipps was cast as Audrey Liddell in the teen drama Dawson’s Creek. She was a series regular in seasons 5 and 6, appearing in 46 episodes, before the show finished in 2003. Her portrayal of Audrey earned Philipps a Teen Choice Awards nomination in the category of “TV – Choice Sidekick”.

Philipps then appeared in several films, including Home Room (2002) and White Chicks (2004). She was cast in the UPN sitcom Love, Inc., in a role originally intended for Shannen Doherty. The show lasted for one season (2005–2006). In 2006, she had a major recurring role as Hope Bobeck on ER, alongside her Freaks and Geeks co-star Linda Cardellini. During her second year on ER, her character was written out as heading to South America to “fulfill her Christian mission”.

Philipps married screenwriter Marc Silverstein in 2007. They have two daughters, born in 2008 and 2013.

From 2009 to 2015, Philipps portrayed Laurie Keller in the television series Cougar Town. She routinely contributed to the Thrilling Adventure Hour, a live stage radio show. Her primary recurring character is the Red Plains Rider.

On a 2010 appearance on Chelsea Lately, Philipps commented that she auditioned for the hit television show Glee just one week after giving birth, following a pregnancy during which she gained 80 pounds.

Philipps starred on the HBO series Vice Principals, which premiered in 2016 and ended in 2017.

In 2017, Philipps signed on as co-lead opposite Casey Wilson in Tina Fey’s comedy pilot, The Sackett Sisters, for NBC, but the series was not picked up.

In 2018 and 2019, Phillips played the role of Sheba Goodman in season 4 of Netflix’s Unbreakable Kimmy Schmidt.

On June 4, 2019 Philipps gave a testimonial before the House Judiciary Committee, defending the right for women to have access to more abortion clinics. In doing so, Philipps talked about her own experience with abortion, saying:

Philipps had a late-night talk show called Busy Tonight, which aired on on E! from October 28, 2018 to May 16, 2019. In August 2020 she began hosting a podcast, Busy Philipps is Doing Her Best, along with former Busy Tonight writers Caissie St. Onge and Shantira Jackson.