Her departure comes as the sophomore comedy was undergoing massive creative changes.
NBC's Up All Night has lost its star.
Christina Applegate has departed the sophomore comedy, The Hollywood Reporter has confirmed.
STORY: 'Up All Night' Adds Episodes, Switches to Multicamera Format
"It's been a great experience working on Up All Night, but the show has taken a different creative direction and I decided it was best for me to move on to other endeavors," Applegate said in a statement Friday. "Working with Lorne Michaels has been a dream come true and I am grateful he brought me into his TV family. I will miss the cast, producers and crew, and wish them the best always."
Ahead of its reboot from a single- to multicamera series, Applegate's departure comes a month after series creator Emily Spivey also parted ways with the second-year comedy. They follow showrunner Tucker Crawley, who was replaced by Nurse Jackie's Linda Wallem as NBC and studio Universal Television opted to make creative changes to the struggling Applegate, Will Arnett and Maya Rudolph series.
Crawley, for his part, replaced original showrunner Jon Pollack. The former departed in December to work as a consulting producer on Fox's The Mindy Project, which is produced by Universal Media Studios.
STORY: NBC's 'Up All Night' Changes Showrunners as Multicamera Switch Nears
NBC announced in December that Up All Night was scheduled to resume production in February following a three-month hiatus, with three additional episodes tacked on to its initial order of 16. The Michaels-produced comedy is amid a transition from single-camera to a generally cheaper and often broader multicamera format, a process that has entailed building new soundstages to be able to film the series in front of a live studio audience.
Up All Night is scheduled to return to NBC in April or May. The creative changes mark the latest for the comedy this year after the Rudolph's talk-show format was ditched in the season two premiere earlier this fall. All of the tweaks come as NBC looks to refresh their comedy brand as a destination for more broadly appealing fare, which entertainment chief Jennifer Salke outlined in an interview with The Hollywood Reporter last month.
Studio Universal Television declined comment on Applegate and the show's future. NBC also declined comment on the show's status.