After high school, Hendricks worked as a receptionist and shampoo girl at a salon before entering a competition to appear on the cover of Seventeen magazine. This resulted in her signing with IMG Models, after which she moved to New York City at age 18, forgoing her pre-acceptance into Virginia Commonwealth University's drama school.

She began modeling in New York, London, and Japan between the ages of 18 and 27 before transitioning into commercials. She lived in London for around a year during this period, living with two friends who were teachers. In her early twenties, she moved with her mother and brother to Los Angeles, California. Initially, she pursued a career in the administrative sector of the music business, but was dissuaded by friends, and kept working as a model before auditioning for acting roles. She appeared in commercials for Carl's Jr. and Dr. Pepper, and starred in the music video for Everclear's "One Hit Wonder" (1997). She was the hand model in the poster for the film American Beauty.

She made her television debut in the MTV anthology series Undressed. Her first starring role was as an intern on Beggars and Choosers, a Showtime comedy series about a group of young professionals that was filmed in Vancouver and ran from 1999 to 2001. She also had a guest role on the series Angel in 2000. She subsequently appeared in the television film The Big Time (2002), and had recurring guest roles on ER (2002), The Court (2003), and Firefly (2002–2003). After a guest appearance on Tru Calling, she was cast as Nicolette Ray in the UPN legal drama Kevin Hill, which aired during the 2004–05 television season.
In perhaps her best-known role to date, Hendricks played office manager Joan Holloway on the AMC series Mad Men, set in a series of fictitious advertising agencies in 1960s New York City. Her performance received critical praise, and earned her six Primetime Emmy nominations for Outstanding Supporting Actress in a Drama Series over the show's seven seasons.

Also in 2007, Hendricks made her feature film debut in La Cucina, a drama film that premiered on Showtime in December 2009, starring Hendricks as a writer. That year, she also starred in the thriller film South of Pico, and appeared in four episodes of the NBC series Life (2007–2008) in the recurring role of Olivia, detective Charlie Crews' soon-to-be stepmother and Ted Earley's love interest.

In 2010, she appeared in the musical video for "The Ghost Inside" on Broken Bells by Broken Bells.

She appeared in a supporting role in the action-thriller Drive (2…

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On October 11, 2009, Hendricks married actor Geoffrey Arend. Ten years later it was announced that they had separated, with a divorce finalized in December 2019. As of 2021, she was in a relationship with camera operator George Bianchini. They announced their engagement in March 2023, and married on April 20, 2024.

Hendricks commented in September 2010 that the media is too focused on women's bodies and not their actual talents. "I was working my butt off on Mad Men and then all anyone was talking about was my body."

• Maron, Marc; Hendricks, Christina (April 15, 2019). Episode 1010. WTF with Marc Maron.