It follows the rise of Harley Quinn, or Dr. Harleen Quinzel, from merely being known as "Joker's girlfriend" to being one of the most famous criminals in the history of Gotham City until she became one of Batman's staunchest opponents.
After Gotham City separates from the United States, a new gang succeeds in taking over the city, so Harley decides to escape and get help in order to restore the city again.
Following their wedding escape, Harley and Ivy take up a long-abandoned secret project of Ivy's before their journey takes them to the scene of an old friend's disappearance and their investigation in it.
Harley faces difficulties adapting to her new duties and investigates the death of one of the good guys before using the Time Sphere to visit the future and predict the imminent apocalypse.