Deschanel was born in Los Angeles, California, to cinematographer and director Caleb Deschanel and actress Mary Jo Deschanel (née Weir). Her younger sister is actress and singer-songwriter Zooey Deschanel. Her paternal grandfather was French, from Oullins, Rhône; her roots also include Swiss, Dutch, English, Irish, and other French ancestry.
Deschanel attended Harvard-Westlake and Crossroads School in Los Angeles before graduating from Boston University's Professional Actors Training Program with a Bachelor of Fine Arts in Theater.
In 1994, Deschanel made her feature film debut in the romantic comedy-drama It Could Happen to You. Her next notable role was as Pam Asbury in Stephen King's horror miniseries Rose Red in 2002. Then she appeared in Cold Mountain, The Alamo, and Glory Road and was named one of "six actresses to watch" by Interview Magazine in 2004.
In 2005, Deschanel was cast as Dr. Temperance Brennan with David Boreanaz as FBI agent Seeley Booth on the Fox crime procedural comedy-drama Bones, based on the novels and the career of forensic anthropologist and author Kathy Reichs, created by Hart Hanson. The series ran for 12 seasons from September 13, 2005 to March 28, 2017. For her performance, she received a 2006 Satellite Award nomination and a 2007 Teen Choice Award nomination. Deschanel and Boreanaz served as co-producers at the start of the show's third season, before becoming producers in the middle of the show's fourth season.
Deschanel, with Alyson Hannigan, Jaime King, Minka Kelly, and Katharine McPhee made a video slumber party featured on FunnyorDie.com to promote regular breast cancer screenings for the organization Stand Up 2 Cancer. In recent years, her passion for animal welfare has led her to providing the narration for My Child Is a Monkey and serving as an associate producer on the documentary film How I Became an Elephant. Deschanel ranked number 72 in The 2012 Hot 100 on AfterEllen.
Deschanel is a vegan and a committed supporter of animal rights causes. She can be seen in an Access Hollywood video at the book launch event of Karen Dawn's Thanking the Monkey: Rethinking the Way We Treat Animals, discussing how vegetarian and vegan diets help the environment, and a video on the homepage of the book's website talking about the importance of animal rights. She collaborated with PETA on a video encouraging mothers to raise their children as vegans. In September 2014, she joined the board of directors at Farm Sanctuary.
Deschanel was raised Roman Catholic, but is no longer practicing, and has expressed agnostic views, saying "I am more of a spiritual person, if anything, and I am of the belief that we don't know, and I'm not going to pretend that I do."
On September 25, 2010, Deschanel married It's Always Sunny in Philadelphia actor and writer David Hornsby in a small private ceremony in the Pacific Palisades area of Los Angeles. On September 21, 2011, Deschanel gave birth to their son, Henry Lamar Hornsby. On June 8, 2015, she gave birth to their second son, Calvin.
Deschanel is best friends with her Bones co-star Michaela Conlin, who played her best friend Angela Montenegro on the show; she is also friends, and has a strong working relationship with her Bones co-star David Boreanaz.