She went on to win six Primetime Emmy Awards for her roles as Lana Gardner in the NBC series Frasier (2000–01), Regina Newley in the ABC sitcom Samantha Who?

Smart's film credits include The Brady Bunch Movie (1995), Sweet Home Alabama (2002), Garden State (2004), I Heart Huckabees (2004), Youth in Revolt (2009), The Accountant (2016), A Simple Favor (2018), and Babylon (2022).

[6] On Season 10 of the television show Who Do You Think You Are?, Smart discovered she is a maternal descendant of Dorcas Hoar, one of the last women convicted of witchcraft during the Salem witch trials.

[3] After graduating from college, Smart began her career appearing in regional theater throughout the Pacific Northwest, including in Washington, Alaska, and Oregon.

[3] In the mid-1970s, she moved to New York City with college friend and fellow actress, Elizabeth Wingate (Lavery), and began working in Off-Broadway and professional regional productions.

[3] In February 1981, Smart appeared in the Broadway production of Piaf playing Marlene Dietrich,[7] a role which she later reprised for the 1984 television version.

[3] In addition to theater, Smart began working in television in several smaller to mid-size guest parts in the late 1970s and early 1980s, appearing on The Facts of Life, Alice, and Remington Steele among several others.

[13] In 1995, Smart was cast as the lead in the comedy series High Society, which co-starred Mary McDonnell and ran for 13 episodes,[3] followed by a role opposite Nancy McKeon in another short-lived CBS sitcom, Style & Substance.

[14] In 2000, Smart was cast as Lana Gardner in the critically acclaimed NBC comedy series Frasier, acting opposite Kelsey Grammer, set in her hometown of Seattle.

[16] Soon after, she landed roles in several high-profile films including Sweet Home Alabama (2002), playing the mother-in-law of Reese Witherspoon,[17] and in the comedy Bringing Down The House (2002), opposite Queen Latifah.

Between 2000 and 2004, Smart played the role of Supervisor of Detectives and ex-wife to Chief Jack Mannion of the Metropolitan Police Department on The District.

[15] She also appeared in several films between 2006 and 2010, including the Curtis Hanson drama, Lucky You (2007), opposite Drew Barrymore; Youth in Revolt (2009); and the independent comedy Barry Munday (2010).

[28] In 2012, Smart was nominated for a Primetime Emmy Award for Outstanding Guest Actress in a Drama Series for her role in Harry's Law.

[30] In 2018, Smart played a guardian angel, to co-star Candace Cameron, in the Hallmark Channel television film A Shoe Addict's Christmas, which aired Sunday November 25, 2018.

In 2019, Smart portrayed Laurie Juspeczyk in the HBO superhero drama limited series Watchmen based on characters from the graphic novel of the same name.

In 2021, Smart appeared in the seven-episode HBO crime drama limited series Mare of Easttown set in a small town in Pennsylvania.

The series stars Kate Winslet as a grizzled detective with a supporting cast that includes Guy Pearce, Julianne Nicholson, and Evan Peters.

Her role as Winslet's mother has earned her critical acclaim with Jackson McHenry of Variety writing, "It's one of those essential truths of TV, as Watchmen and Legion displayed recently, that if you need a tough-as-nails broad, you hire Jean Smart.

Smart has the voice and the timing to play a stern matriarch, and whenever she's onscreen in Mare of Easttown, she wrenches away the spotlight like she's grabbing a juice box.

[40] Zach Vasquez of The Guardian wrote of her hosting duties, "Smart is no slouch – a great dramatic and comedic actor of stage and screen, she nails her monologue, delivering jokes like the pro comic she plays on Hacks, before singing a rendition of Cole Porter’s "I Happen to Like New York.

Smart also worked with her husband in season 5 of 24; he played Captain Stan Cotter in one episode, while she starred in the main cast role of First Lady Martha Logan.