Deschanel is known for her deadpan roles in comedy films such as The Good Girl (2002), The New Guy (2002), Elf (2003), The Hitchhiker's Guide to the Galaxy (2005), Failure to Launch (2006), Yes Man (2008), 500 Days of Summer (2009), and Our Idiot Brother (2011).

[3][4][5] She has also ventured into dramatic film territory with Manic (2001), All the Real Girls (2003), Winter Passing (2005), Bridge to Terabithia (2007), The Happening (2008), and The Driftless Area (2015).

[12][16][time needed] She sang throughout high school, planning to pursue a career in musical theatre and attending French Woods Festival of the Performing Arts.

She made her film debut in Lawrence Kasdan's comedy Mumford (1999), revolving around the neurotic residents in a small town and co-starring Hope Davis, Jason Lee, Alfre Woodard and Mary McDonnell.

[20] Deschanel co-starred in Cameron Crowe's semi-autobiographical Almost Famous (2000), where she played Anita Miller, the rebellious older sister of a teenage journalist.

[22] Following early notice, Deschanel took on supporting parts in four feature films released throughout 2002: Big Trouble, The New Guy, The Good Girl, and Abandon.

Deschanel portrayed a cynical, plain-spoken young woman working in a big-box store in the black dramedy The Good Girl, opposite Jennifer Aniston and Jake Gyllenhaal.

"[11] Deschanel obtained her first leading film role debut in the independent drama All the Real Girls (2003) as Noel, a sexually curious 18-year-old virgin who has a life-changing romance with an aimless 22-year-old.

The actress does a wonderful job presenting a young woman who is trying, with varying degrees of success, to give voice to all sorts of things she has never felt or expressed before".

[24] Also in 2003, Deschanel starred opposite Will Ferrell in the Christmas comedy Elf as a deadpan department store worker and the love interest of a man raised by Santa's elves.

[27] In 2004, Deschanel starred in Eulogy, and in 2005 played Trillian in the film adaptation of Douglas Adams's science fiction novel The Hitchhiker's Guide to the Galaxy.

She had a small role as Dorothy Evans in the revisionist Western The Assassination of Jesse James by the Coward Robert Ford and starred in the B comedy Flakes, which was released in only one theater.

[31] Deschanel starred as DG in the Syfy miniseries Tin Man, a re-imagined science fiction version of The Wonderful Wizard of Oz.

Despite largely negative reviews, critic Roger Ebert felt that Wahlberg and Deschanel's performances "bring a quiet dignity to their characters",[34] and globally, the film made US$163 million.

[35] She starred in the independent comedy Gigantic (2008), which screened at the Toronto International Film Festival and was distributed for a limited release in certain parts of the United States only.

[39][40][41] Mark Adams of the Daily Mirror found the film to be a "modern romance for grown-ups" and a "sweet-natured, funny, deeply-romantic tale" blessed with "top-notch performances by Deschanel and Gordon-Levitt, who are both charming and have real chemistry".

[43][44] Deschanel was originally the top choice for Janet van Dyne / The Wasp in an early draft of Joss Whedon's The Avengers in which she would have played a prominent role.

However, once Scarlett Johansson was cast as Natasha Romanoff / Black Widow, Deschanel was no longer in consideration to portray the Wasp with Janet's daughter Hope van Dyne taking up the mantle in the Infinity Saga, played by Evangeline Lilly.

[48] Describing her role, Roger Ebert noted in its review for the film: "[Deschanel is] brought onstage, quickly kidnapped by an evil sorcerer, spends a good deal of time as a captive in his lair, is rescued and lives happily ever after.

[49] Deschanel signed on to star as a bubbly and offbeat teacher Jessica "Jess" Day on the Fox sitcom New Girl, created by Elizabeth Meriwether.

[51] The series premiered in September 2011, and USA Today described her performance as "a role tailored to launch her from respected indie actor to certified [television] star, Deschanel soars, combining well-honed skills with a natural charm".

[58] She obtained the role of a mysterious woman in the neo-noir drama The Driftless Area (2015), screened at the Tribeca Film Festival and released on video on demand and home media.

[62] In January 2022, she began cohosting Welcome to Our Show, a New Girl rewatch podcast with co-stars Hannah Simone and Lamorne Morris, distributed by IHeartRadio.

[67] In March 2007, Deschanel contributed vocals to two songs "Slowly" and "Ask Her to Dance" on the album Nighttiming by Jason Schwartzman's band Coconut Records.

[73] Deschanel and M. Ward both featured on The Place We Ran From (2010), the album by Snow Patrol member Gary Lightbody's side project, Tired Pony.

[84] Response towards the album was positive, with Robert Hamm for Alternative Press writing that Deschanel "is a delight, at times coy and romantic, and in other moments, moody and pensive".

In Elf (2003), she sings "Baby, It's Cold Outside" with Will Ferrell in the bathroom shower scene, "Auld Lang Syne" with James Caan on piano and with Leon Redbone on the soundtrack.

Her piano composition "Bittersuite" was used thematically in the dark dramedy Winter Passing (2006), in which she co starred with Ferrell and Ed Harris, and also sings "My Bonnie Lies over the Ocean" in the film.

[88] In 2007, other singing credits followed: the television musical Once Upon a Mattress ("An Opening for a Princess", "In a Little While", "Normandy", and "Yesterday I Loved You");[89] an old cabaret song in The Assassination of Jesse James by the Coward Robert Ford ("A Bird in a Gilded Cage"); and the short film Raving ("Hello, Dolly!").

Deschanel and Joseph Gordon-Levitt did a music video, called Bank Dance, directed by 500 Days of Summer director Marc Webb, to accompany the film.