After appearing in several roles since early childhood, Applegate gained recognition in the late 1980s for playing Kelly Bundy in the FOX sitcom Married... with Children (1987–1997).

Applegate starred in the title role of the sitcom Jesse (1998–2000), which earned her a Golden Globe Award nomination.

Her father, Robert William "Bobby" Applegate, was a staff producer at Dot Records;[2] her mother, Nancy Priddy, is a singer and actress.

[4] Applegate made her television debut in 1972 alongside her mother in the soap opera Days of Our Lives and starred in a commercial for Playtex baby bottles at 3 months old.

From 1987 to 1997, Applegate played the ditzy, sexually promiscuous daughter, Kelly Bundy, on 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.

When Married... with Children was cancelled in 1997, producers pitched a spinoff centered on Kelly Bundy, but Applegate declined.

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.

[10] Applegate played 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).

After playing Cameron Diaz's level-headed best friend, Courtney Rockcliffe, in The Sweetest Thing (2002), she appeared in Heroes (2002), the romantic airplane comedy View from the Top (2003), the true-crime film Wonderland (2003) based on the Wonderland murders, and the Gram Parsons biopic Grand Theft Parsons (2003).

She won the Primetime Emmy Award from two nominations for Outstanding Guest Actress in a Comedy Series[11] for her performance in "The One with Rachel's Other Sister."

Applegate received recognition for her portrayal of anchorwoman Veronica Corningstone in the 2004 comedy films Anchorman: The Legend of Ron Burgundy and Wake Up, Ron Burgundy: The Lost Movie, an alternative film comprising alternate takes and deleted scenes and story elements.

Applegate has performed on stage in The Axeman's Jazz, Nobody Leaves Empty Handed, The Runthrough, and John Cassavetes' The Third Day (co-starring Gena Rowlands).

[13] In 2006, Applegate appeared in Jessica Simpson's music video for "A Public Affair" with Eva Longoria, Ryan Seacrest, and Christina Milian.

The series co-starred Jean Smart, Jennifer Esposito, and Melissa McCarthy and 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.

[19] 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?.

[20] In 2013, Applegate reprised her role as Veronica Corningstone in the comedy sequel film Anchorman 2: The Legend Continues.

In 2015, she starred with Ed Helms in the National Lampoon sequel Vacation, the fifth full-length movie episode of the road-trip comedies.

In 2016, she starred as Gwendolyn James in the comedy film Bad Moms with Mila Kunis, Kristen Bell, and Kathryn Hahn.

[26] In 2024, Applegate began a podcast with fellow actress with MS Jamie-Lynn Sigler called MeSsy about their friendship based on the condition.

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',"[36] which included a change to a more healthy diet.

[37] The disease heavily affected her ability to perform in the final season of Dead to Me, for whose success she credits her co-star Linda Cardellini and showrunner Liz Feldman's support and openness in making reasonable adjustments to her filming schedule.

[41] In 2003, she was the spokesman for the Lee National Denim Day, which raises millions of dollars for breast cancer education and research.