In 1985, she took her first step toward “film production by pursuing a position as a commercial and music video production assistant.” From 1996 to 1998, and from 2000 to 2002, Khouri served on the Writers Guild of America board of directors; she sat on the board of trustees of the Writer’s Guild Foundation from 2001 to 2004. She was a member of Hollywood Women's Political Committee, Fairness and Accuracy in Reporting Women's Media Watch Project.

On June 2, 1990, she married David Weaver Warfield, a Writer and a Producer. She later divorced him, and married musician T Bone Burnett in 2009.

Her second film as a Writer, the romantic comedy-drama Something to Talk About (1995), earned mixed reviews from critics.

In June 2002, Khouri made her directorial debut with her adaptation of Divine Secrets of the Ya-Ya Sisterhood, which grossed a total of $73,839,240 worldwide. The film opened at number two in the box office behind The Sum of All Fears's second weekend.

In 2006, Khouri created, wrote and directed the pilot for the legal television series Hollis & Rae that was produced by Steven Bochco.

Khouri directed Mad Money in 2008, a crime-caper film starring Diane Keaton, Queen Latifah, and Katie Holmes.

In 2012 she developed ABC’s country music drama series, Nashville, starring Connie Britton and Hayden Panettiere. Khouri's husband T Bone Burnett was the show's executive music Producer and Composer for the first season. Leaving the show shortly after the first season production wrapped, Burnett later stated that he was upset with television executives' treatment of his wife. His assistant and the managing Producer Buddy Miller took over for Burnett in season two. Nashville received positive reviews from critics, and Khouri continued on the show without Burnett's involvement.

The National Women's History Museum (NWHM) is a non-profit organization that recognizes powerful women who contribute toward feminist filmmaking, such as Callie Khouri and Susan Sarandon. It also receives support, as well as generous donations, from other women such as Shonda Rhimes, Meryl Streep, and Frances Fisher. On August 23, 2014, Callie Khouri was honored by the National Women’s History Museum and NWHM Los Angeles Council in "Women Making History Brunch" at the Skirball Cultural Center in Los Angeles, California, for winning an Academy Award, Golden Globe, and WGA. “She’s revolutionary,” said Geena Davis on working with Khouri, who also is the creator and executive Producer of Nashville." “She creates characters that are in charge of their own fate to the bitter end. Female characters who are in charge of themselves.”

Aside from teaching and film-making, Khouri devotes time to feminist organizations. "Don’t you think talking about it is important, making the next generation understand that things are still not right for women?" says Khouri. “I feel like I owe aspiring Writers at least the warning that they are picking maybe the hardest thing there is to do in the Business,” she says. “It doesn’t matter any more how good you are. In some ways, it never really did. Bad movies get made as often as good ones, but so few movies get made now, period. If you write for a studio, you may be one of eight Writers, so it’s not like you can have an artistic vision of your own and achieve it solely through screenwriting. I was very lucky because Ridley really wanted to tell Thelma & Louise. He wanted to make the movie I wanted to make. But often times that’s not the case at all. They think your script is a good idea and that’s all. So they buy it and then they hire two or three other people to take a whack at it and it can be a very disappointing thing."