Applegate starred in the ABC sitcom 'Samantha Who?,' playing a woman who develops amnesia and tries to rediscover her past. The role earned her Primetime Emmy Award nominations and a People's Choice Award. The show was canceled after two seasons.

Applegate starred in the NBC sitcom 'Up All Night', alongside Will Arnett and Maya Rudolph. She played Reagan Brinkley, a working mother navigating parenthood. The show was initially well-received, but faced creative changes and was eventually canceled.

Applegate starred in and executive produced the Netflix dark comedy series 'Dead to Me,' alongside Linda Cardellini. Her performance as Jen Harding, a grieving widow, earned her widespread critical acclaim, including Primetime Emmy Award nominations, Golden Globe Award nominations, and Screen Actors Guild Awards nominations. It is widely considered to be among the best work of her career.