Cuoco made the announcement on Wednesday night during New York Comic Con, complete with a promotional video featuring her debut as the character in the animated series slated for the DC Universe streaming service.
While Harley is known for her wild and unpredictable humor, the role is still quite a departure from Cuoco's "Big Bang" character, Penny. For one, DC Universe is not a major broadcast network, and that means greater freedom in content.
"This has been the edgiest, darkest thing I think I've ever done in my career," Cuoco said of the role, as reported by USA Today. "I have cussed and screamed more than I think I ever have, and it has been a fricking blast. It's very freeing."
Harley's feisty attitude is all over the promo released with the announcement. It features Harley and her best friend -- maybe more? -- Poison Ivy sitting in a jail cell while Harley breaks the fourth wall and talks about her new show. "Unlike that 'Deapdool' cartoon, it's actually coming out," she says at one point, taking a jab at Donald Glover's scrapped effort.
The teaser also poked fun at toxic fanboys, the bleakness of DC films, and even Batman. "The guy's a real buzzkill," Harley says after he makes a surprise cameo, voiced once again by Diedrich Bader ("Batman: The Brave and the Bold").
Margot Robbie's take on the Joker's paramour in the 2016's "Suicide Squad" was considered by many to be one of the few redeeming elements of that disastrous film. First introduced in "Batman: The Animated Series," Harley Quinn proved so popular she made her way into the DC Universe of comics with her own title, and is now headlining her own show.
While her problematic relationship with the Joker has largely defined the character since her debut in 1992, Cuoco promises they're pushing her into new territory on DC Universe. She also serves as an executive producer on "Harley Quinn."
"She's dating the Joker, and then they have a big breakup," Cuoco explained. "She decides, 'Screw Joker, I'm going to take over Gotham City by myself.' And that's kind of how this series starts, how you don't need a man to help you ruin the city. You can ruin it all by yourself."
"Harley Quinn" has assembled an all-star cast, including Jason Alexander, Lake Bell, Giancarlo Esposito, Ron Funches, Tony Hale, Natalie Morales, Jim Rash, JB Smoove, Wanda Sykes, Alan Tudyk, and Christopher Meloni. No premiere date has been announced.