For her work on The Simpsons, Smith received a Primetime Emmy Award for Outstanding Voice-Over Performance in 1992.

In 2004, Smith performed an off-Broadway one-woman show entitled More at the Union Square Theatre in New York City.

Smith starred in and served as executive producer for the independent romantic comedy Waiting For Ophelia, which had its world premiere at the Phoenix Film Festival in April 2009.

[2][3] Her mother, Martha Mayor, was a paper conservator for the Freer and Sackler Galleries at the Smithsonian Institution.

[12][13] After appearances in a number of school plays, she joined the local Arena Stage theater group on an apprenticeship, featuring in their production of Peter Pan.

[12] She moved to New York City in 1984 and appeared in the Broadway production of Tom Stoppard's play The Real Thing alongside Jeremy Irons and Glenn Close.

The film was a box office bomb and critically panned, although Smith "thought it would be the movie that launched my career.

[10] However, the following year, she played Connie in Stephen King's Maximum Overdrive (1986), noting it was "truly a dreadful film, but I had a great part in it.

[10] In Los Angeles, Smith appeared in theatrical productions of Living on Salvation Street, for which she was paid $14 for each performance,[13] Boys and Girls/Men and Women, and How the Other Half Loves, and played the recurring role of Louella Waters on the Showtime series Brothers.

Smith had initially been asked to audition for the role of Lisa's brother Bart, but casting director Bonita Pietila thought her voice was too high.

[13] Lisa is the only regular character voiced by Smith, although in some earlier episodes, she provided some of Maggie's squeaks and occasional speaking parts.

The Emmy for Outstanding Voice-Over Performance is a Creative Arts and not handed out during the primetime telecast and, prior to 2009, was a juried award without nominations.

"[26] The show's creator Matt Groening has called Smith very similar to Lisa: "Yeardley has strong moral views about her character.

'"[10] Writer Jay Kogen praised her performance on the show, particularly in the episode "Lisa's Substitute", as able "to move past comedy to something really strong and serious and dramatic".

[10] From 1991 to 1994, alongside The Simpsons, Smith was one of the lead cast members in the sitcom Herman's Head as Louise.

[12] Her other television roles include recurring appearances as Marlene on Dharma & Greg, and Penny in two episodes of Dead Like Me.

"[10] In 2004, Smith performed her own off-Broadway one-woman show entitled More at the Union Square Theatre in New York City.

Directed by Judith Ivey,[28] the play is about her mixed feelings over the success of The Simpsons, her parents, her relationships, and her struggles with bulimia.

[2][26] The New York Times critic Margo Jefferson called it an "appealing if overlong show", adding that "The career narrative needed shortening.

It is refreshing to hear a celebrity talk cleanly about being fame-driven and about not getting the degree or the kind of fame you craved.

[29] Smith starred in and served as executive producer for the independent romantic comedy Waiting for Ophelia, which was released in 2009.

[31][32] On March 30, 2019, Smith was honored with the Human Rights Campaign's National Leadership Award in Los Angeles for her work as an advocate of the LGBT community.

[37][38] Smith recommended that people of differing political views should be able to work together on gun control, promoting gay rights and environmentalism.

[40] In a 1997 interview with The Daily Targum, Smith stated "I am shy, but I have an extroverted persona which I can draw on when I need to," and that she is a "private" actress.

[11] She married Daniel Erickson in 2002; the marriage lasted for six years and Smith filed for divorce on May 21, 2008, citing irreconcilable differences.

[44][45] On June 11, 2022, Smith married one of the co-hosts of her podcast, Small Town Dicks, Detective (Ret) Dan Grice.