For a few years starting in 2001, Deschanel performed in the jazz cabaret act If All the Stars Were Pretty Babies with fellow actress Samantha Shelton. She plays keyboards, percussion, banjo and ukulele, and has sung in several of her films. Deschanel's debut album Volume One (recorded with M. Ward under the moniker She & Him) was released on March 18, 2008. The follow up album Volume Two was released in the U.S. on March 23, 2010. She is married to Death Cab For Cutie frontman Ben Gibbard.

Zooey Deschanel, born in Los Angeles, California, is the daughter of cinematographer/director Caleb Deschanel and actress Mary Jo Deschanel (née Weir). She is of French and Irish descent. She was named after Zooey Glass, the male protagonist of J. D. Salinger's 1961 novella Franny and Zooey. Her older sister Emily Deschanel is also an actress, and stars in the TV series Bones, where she is also listed in the credits as a producer.

Deschanel lived in lower Los Angeles, but spent much of her childhood traveling because her father shot films on location; she later said that she "hated all the traveling[...] I'm really happy now that I had the experience, but at the time I was just so miserable to have to leave my friends in Los Angeles and go to places where they didn't have any food I liked or things I was used to." She grew up in Canada, Yugoslavia, England and South Africa. She attended Crossroads, a private preparatory school in Santa Monica, California, where she befriended future co-stars Jake Gyllenhaal and Kate Hudson. She sang throughout high school, planning to pursue a career in musical theatre. She attended Northwestern University for seven months before dropping out to work as an actress.

Deschanel appeared in a guest role on the television series Veronica's Closet before making her film debut in Lawrence Kasdan's 1999 comedy Mumford, and later in the year she appeared (non-singing) in the music video for The Offspring's single "She's Got Issues". In her second film, director Cameron Crowe's semi-autobiographical Almost Famous (2000), Deschanel played Anita Miller, the protagonist's rebellious older sister. The film received critical praise, but was not a box office success.

Deschanel played supporting roles in a series of films that included Manic (2001), with Don Cheadle and Joseph Gordon-Levitt, Big Trouble (2002), with Tim Allen and Rene Russo, Abandon (2002) alongside Katie Holmes, Benjamin Bratt and Melanie Lynskey, and The Good Girl (2002) alongside Jennifer Aniston and Jake Gyllenhaal. In late 2002, The New York Times reported that Deschanel was "one of Hollywood's most sought-after young stars," and the Los Angeles Times wrote in early 2003 that Deschanel had become a recognizable type, due to "her deadpan, sardonic and scene-stealing [film] performances" as the protagonist's best friend. Deschanel objected to her typecasting, arguing, "A lot of these roles are just a formula idea of somebody's best friend, and it's like, I don't even have that many friends. In high school, I stayed home all the time, so I don't know how I'm everybody's best friend now."

Deschanel appeared in Frasier, starring as Roz's out-of-control cousin, Jen, in the Season 10 episode 'Kissing Cousin' in 2002. That year she also appeared in the film The New Guy as Nora, the guitar player in the lead character's band, Suburban Funk.

After turning down several supporting roles, Deschanel played her first lead role in All the Real Girls (2003). Her performance as Noel, a sexually curious 18-year-old virgin who has a life-changing romance with an aimless 22-year-old, received critical praise, and she received an Independent Spirit nomination for Best Actress. Later in 2003, Deschanel played a deadpan department store worker opposite Will Ferrell in the comedy Elf, which became a box office hit.

In 2004, Deschanel starred in Eulogy, and in 2005 as Trillian in the film adaptation of Douglas Adams' science fiction novel The Hitchhiker's Guide to the Galaxy. Deschanel then played Sarah Jessica Parker's neurotic roommate in Failure to Launch (2006), and appeared on four episodes of the Showtime television series Weeds from 2006 to 2007, playing Andy Botwin's quirky ex-girlfriend, Kat. In September 2006, Variety announced that Deschanel would play 1960s singer Janis Joplin in the film The Gospel According to Janis, to be co-written and directed by Penelope Spheeris. Deschanel planned to sing all of Joplin's songs, and took four months of singing lessons "to approximate Joplin's gritty vocals." The film, scheduled to begin shooting on November 13, 2006, was postponed indefinitely. However, the project is now back on track and will be released in 2012.

In 2007, Deschanel appeared in two children's films, Bridge to Terabithia, in which she played Jesse's quirky music teacher and the animated film Surf's Up, in which she voiced a penguin named Lani Aliikai. She played DG, the lead in the Sci Fi Channel miniseries Tin Man, a re-imagined science fiction version of L. Frank Baum's children's book The Wonderful Wizard of Oz. Tin Man aired on Sci Fi in December 2007. Deschanel also narrated the children's book Players in Pigtails.

On April 27, 2008, she performed on The Simpsons, playing the role of Mary, Cletus's daughter, and in June that year, she starred opposite Mark Wahlberg in M. Night Shyamalan's poorly received environmental thriller The Happening.