She is best known for her leading role as Dharma on the ABC sitcom Dharma & Greg (1997–2002), for which she received the Golden Globe Award for Best Actress – Television Series Musical or Comedy in 1999, and three nominations for the Primetime Emmy Award for Outstanding Lead Actress in a Comedy Series.

Elfman has also played leading roles on other television comedies, including Courting Alex (2006), Accidentally on Purpose (2009–2010), 1600 Penn (2012–2013), Growing Up Fisher (2014), and Imaginary Mary (2017).

[3] Elfman's paternal uncle is Tony Butala, lead singer of the American vocal trio The Lettermen since 1958.

After appearing in television commercials, Elfman co-starred in the made-for-television movie Double Deception (1993) and guest-starred on Roseanne, NYPD Blue, Almost Perfect and Murder One.

In 1996, she was cast as a lead character alongside Molly Ringwald and Lauren Graham in the short-lived ABC sitcom Townies.

[7] The following year, she made her big screen debut appearing in the black comedy film, Grosse Pointe Blank.

[14] The following year, she starred in the romantic comedy film Keeping the Faith opposite Ben Stiller and Edward Norton (who also directed).

[17] Elfman received Satellite Award for Best Actress – Motion Picture Musical or Comedy nomination for her performance.

In 2001, she appeared in the romantic comedy film Town & Country, a $105 million production budget box office bomb.

After Dharma & Greg, Elfman played against the type role as a psychotic woman in the made-for-television thriller film, Obsessed (2002).

In 2013, Elfman starred in the NBC comedy series, 1600 Penn and later in Growing Up Fisher, which were each cancelled after a single season.

[26] In 2018, Elfman was cast in the AMC horror drama series, Fear the Walking Dead playing the mysterious nurse June "Naomi / Laura" Dorie.

[31] In February 1991, she met actor Bodhi Pine Elfman (né Saboff) during an audition for a Sprite commercial.

On March 27, 2008, she and actor Charlie Sheen co-hosted the Scientology-affiliated New York Rescue Workers Detoxification Project charity event at Geisha House in Hollywood.