After splitting with the Joker, Harley Quinn finds herself unprotected and on the hit list of every thug in Gotham City. When the sadistic crime lord Roman Sionis, also known as Black Mask, places a target on a young girl named Cassandra Cain, the city turns upside down looking for her. Harley steps in and takes Cassandra under her wing after the girl steals something valuable from Sionis, drawing the wrath of Gotham's underbelly towards them both. With Harley's unpredictable nature, the duo's chances of survival begin to dwindle.

In the meantime, disgruntled detective Renee Montoya is hot on the trail of Sionis and his enforcer, Victor Zsasz, who are wreaking havoc across the city. She encounters Helena Bertinelli, the crossbow-wielding vigilante with a vendetta, and the enigmatic songstress Dinah Lance, who has a voice with the power to shatter glass. These women, each with their distinct moral codes and capabilities, are drawn together by the escalating threat of Sionis. As their paths converge, they must learn to work together if they want to take down the patriarchal crime lord who's been terrorizing Gotham.