Applegate made her television debut in 1972, alongside her mother in the soap opera Days of Our Lives. She later starred in a commercial for Playtex baby bottles at 3 and 5 months, respectively, and made her film debut in the 1981 horror film Jaws of Satan (or King Cobra), followed by 1981’s Beatlemania. She debuted in a television film as young Grace Kelly in the biopic Grace Kelly (1983), and appeared in her first television series in Showtime’s political comedy Washingtoon (1985), in which she played a congressman’s daughter. She was also seen as a guest in the series Father Murphy (1981), Charles in Charge (1984–1985), and Silver Spoons (1986). In 1986, Applegate won the role of Robin Kennedy, a policeman’s daughter, in the police drama series Heart of the City (1986–1987). For her performance, Applegate received a Young Artist Award. She was also seen in guest-starring roles on several other television series, such as All is Forgiven, Still the Beaver, Amazing Stories, and Family Ties.

From 1987 to 1997, Applegate played the role of the ditzy, sexually promiscuous daughter Kelly Bundy on the Fox’s first sitcom, Married… with Children. While working on the series, Applegate was seen in Dance ’til Dawn (1988) and Streets (1990), in which a teenage drug addict is stalked by a psychotic police officer. She guest-starred in 21 Jump Street (1988) and Top of the Heap (1991), and also hosted Saturday Night Live (1993) and MADtv (1996).

Applegate has supported Entertainment Industry Foundation, Adopt-A-Classroom, The Motion Picture and Television Fund Foundation, World Animal Protection, and the Trevor Project. In 1992, she joined other celebrities in a benefit show for a Hollywood children’s charity, acting as a special guest assistant to a local magician and taking part in a number of illusions, including being sawn in half. In 2003, she was the spokesman for the Lee National Denim Day, which raises millions of dollars for breast cancer education and research. Following her diagnosis with breast cancer, Applegate appeared on a television special titled Stand Up to Cancer, designed to raise funds for breast cancer research. The one-hour special was broadcast on CBS, NBC, and ABC television networks on September 5, 2008. In 2009, she announced her plans to return as the ambassador for Lee National Denim Day. Also in 2009, she founded Right Action for Women, a charitable foundation dedicated to breast-cancer screening for women, and focused on the type of MRI scan that saved her life. In February 2015, Applegate was awarded the Saint Vintage Love Cures Award from unite4:humanity and Saint Vintage, for her dedication to and work with Right Action for Women.

Applegate was one of the founding members of The Pussycat Dolls, which debuted at Johnny Depp’s Viper Room on the Sunset Strip in 1995. Applegate emceed for the group when they moved to The Roxy Theatre in 2002. In 1996, Applegate auditioned for the role of Rose in James Cameron’s blockbuster hit Titanic, but lost to Kate Winslet. In 1998, Applegate began portraying the title role in the NBC sitcom Jesse. The series debuted in 1998 and received rave reviews. Applegate received the People’s Choice Award for Favorite Female Performer in a New Television Series and the TV Guide Award for Favorite Star of a New Series, as well as a nomination at the Golden Globe Awards for Best Actress in a Comedy. The series was cancelled in 2000.

The character of Sue Ellen Crandell in the black comedy feature Don’t Tell Mom the Babysitter’s Dead (1991) was Applegate’s first starring role in a mainstream film, playing a rebellious teenager who is forced to take care of siblings after their summer babysitter dies. Applegate followed with roles in films such as Vibrations (1995), Across the Moon (1995), Wild Bill (1995), Tim Burton’s Mars Attacks! (1996), and Gregg Araki’s Nowhere (1997). After the sitcom Married… with Children was cancelled in May 1997, Applegate starred as Claudine Van Doozen in the independent feature Claudine’s Return (or Kiss of Fire), was cast in the action-comedy The Big Hit, and played the fiancée of a mob boss in the Mafia satire Jane Austen’s Mafia (1998).

On October 20, 2001, Applegate married actor Johnathon Schaech in Palm Springs, California. Schaech filed for divorce in December 2005, citing irreconcilable differences, and the divorce was finalized in August 2007. In 2009 she began dating Dutch musician Martyn LeNoble. The couple became engaged on Valentine’s Day 2010, and married on February 23, 2013, at their Los Angeles home. It is the second marriage for both. They have one daughter, Sadie Grace, born in January 2011. Applegate is a vegetarian, and in 2007, appeared in an anti-fur advertisement for PETA.

The new millennium had Applegate playing the dual role of a 12th-century noblewoman, Princess Rosalind, and her 21st-century descendant, Julia Malfete, in the time-travel comedy Just Visiting (2001). She was Princess Gwendolyn and Kate in the movie Prince Charming (2001). After playing Cameron Diaz’s level-headed best friend, Courtney Rockcliffe, in The Sweetest Thing (2002), Applegate continued to play roles in such films as Heroes (2002), and the romantic airplane comedy View from the Top (2003), as well as in the true-crime film Wonderland (2003), based on the Wonderland murders, and the Gram Parsons biopic Grand Theft Parsons (2003). In 2004 Applegate starred alongside Ben Affleck in the holiday comedy Surviving Christmas, and alongside Matt Dillon in Employee of the Month. Behind the screen, she was the executive producer of Comforters, Miserable (2001).

Applegate guest-starred on two episodes of Friends, in the ninth (2002) and tenth (2003) seasons, titled “The One with Rachel’s Other Sister” and “The One Where Rachel’s Sister Babysits” as Amy Green, Rachel Green’s (Jennifer Aniston) sister. She won the Primetime Emmy Award (from two nominations) for Outstanding Guest Actress in a Comedy Series, for her performance in “The One with Rachel’s Other Sister.” She also received recognition for her portrayal of anchorwoman Veronica Corningstone in the 2004 comedy film Anchorman: The Legend of Ron Burgundy, and its counterpart film Wake Up, Ron Burgundy: The Lost Movie, which is an alternative film comprising alternate takes and deleted scenes and story elements.

In addition to her screen work, Applegate has performed on stage in such productions as The Axeman’s Jazz, Nobody Leaves Empty Handed, and The Runthrough, as well as John Cassavetes’ The Third Day (co-starring Gena Rowlands). In 2004 she debuted on the Broadway stage playing the title role of Charity Hope Valentine in a revival of the 1966 musical Sweet Charity. In late April 2005, she also took part in the annual Broadway Cares’ Easter Bonnet Competition, being sawed in half by a magician in their Clearly Impossible sawing illusion. Sweet Charity ended its Broadway run on December 31, 2005. Applegate eventually took home the 2005 Theatre World Award and was nominated for a 2005 Tony Award for Best Actress in a Musical.

While appearing in Sweet Charity, Applegate broke her foot, and it was announced that the musical would close during previews. She persuaded the producers to rescind their decision and on April 18, 2005, she made her Broadway debut. Because of her injury, Applegate had to wear special shoes to prevent another incident, and in a 2013 interview said that because of what happened, she “actually can’t dance anymore. And that is sad for me because I always wanted to go back. But I probably won’t be able to.” She does dance whenever the opportunity presents, but cannot do any more strenuous roles.

In 2006, Applegate appeared in Jessica Simpson’s music video “A Public Affair” alongside Eva Longoria, Ryan Seacrest, and Christina Milian. She starred in the ABC comedy Samantha Who?, from October 15, 2007 until it was cancelled on May 18, 2009. The series co-starred Jean Smart, Jennifer Esposito, and Melissa McCarthy. The series focused on a 30-year-old, who after a hit-and-run accident, develops amnesia and has to rediscover her life, her relationships, and herself. For her performance, she received two nominations for the Primetime Emmy Award for Outstanding Lead Actress in a Comedy Series and two nominations for the Golden Globe Award for Best Actress – Television Series Musical or Comedy. Shortly after the cancellation was announced, Applegate began a campaign to get the show back into production, which failed. Applegate topped the list of People’s Most Beautiful People in 2009. Applegate appeared with her television brother David Faustino (Bud Bundy from Married… with Children) in an episode of Faustino’s comedy series Star-ving.

On August 3, 2008, People reported that Applegate had been diagnosed with breast cancer. This was confirmed by her representative who said in a statement, “Christina Applegate was diagnosed with an early stage of breast cancer. Benefiting from early detection through a doctor-ordered MRI, the cancer is not life-threatening. Christina is following the recommended treatment of her doctors and will have a full recovery. No further statement will be issued at this time.” On August 19, 2008, it was announced that Applegate was cancer-free after a double mastectomy, though cancer was found in only one breast. She has an inherited genetic trait, a BRCA1 mutation, which can trigger breast and ovary cancer. Her mother, Nancy Priddy, is a breast cancer survivor. Applegate said when she first was diagnosed, “I was just shaking and then also immediately, I had to go into ‘take-care-of-business-mode,’ which included a change to a more healthy diet.”

Applegate starred in the NBC sitcom Up All Night, with Maya Rudolph and Will Arnett. The show debuted on September 14, 2011. On February 8, 2013, she left the series after its second-season hiatus, which was leading into a planned format change. The series was ultimately cancelled.

On July 31, 2013, Applegate was featured on the second episode of the fourth season of the revived American version of the TLC series Who Do You Think You Are?. The broadcast centered on Applegate trying to find out for her father, Robert Applegate, about his mother, Lavina Applegate Walton, who was mysteriously absent for most of her son’s life and who died early in his life. Applegate also hoped to find out if the hearsay concerning her grandmother’s death were true. The actress discovered that Walton died in 1955 from tuberculosis and alcohol-related cirrhosis. Also in 2013, Applegate reprised her role as Veronica Corningstone in the comedy sequel film Anchorman 2: The Legend Continues. The film received positive reviews from critics and was a box office success. The following year, she had a starring voice role as Mary Beth in the animated musical fantasy film The Book of Life.

In 2015, Applegate starred with Ed Helms in the National Lampoon sequel Vacation, the fifth full-length movie episode of the road-trip comedies. Helms and Applegate played Rusty Griswold and his wife Debbie, who with their two sons take a trip to Walley World, just as Rusty did with his parents in the 1983 original film, National Lampoon’s Vacation. The film was poorly reviewed but was a box office success. In 2016, she starred as Gwendolyn James in the comedy film Bad Moms, opposite Mila Kunis, Kristen Bell, and Kathryn Hahn. The film earned mixed reviews from critics and was a box office success. She reprised her role for a cameo appearance in the sequel A Bad Moms Christmas, which was released in November 2017.

In July 2018, Applegate was cast to co-star with Linda Cardellini in the Netflix dark comedy series Dead to Me. She also executive produced the series, alongside Will Ferrell, Adam McKay, and Jessica Elbaum. The series received critical acclaim upon its release. Applegate received two nominations for the Primetime Emmy Award for Outstanding Lead Actress in a Comedy Series for her performance in seasons one and two of the series. She also earned Golden Globe Award, Screen Actors Guild Award, and TCA Award nominations.