Karen is shopping at a convenience store during which a robbery occurs. Her niece is kidnapped and left seriously injured in hospital. When one of the perpetrators is released, Karen decides to go on a murderous trail of revenge.

The series is set in New Gotham City, several years after it has been apparently abandoned by Batman. In his absence, Huntress, Oracle and Dinah are now the protectors of New Gotham: the Birds of Prey, and had taken over his war on crime. They are joined by Alfred Pennyworth, who serves Helena as she is heir to the Wayne estate; and Detective Jesse Reese, a police officer confronted with crimes and abilities he cannot explain. A central feature of the series is the concept of metahumans: individuals born with powers that cannot be explained. No two metahumans have the same abilities (unless hereditary), and there exists a whole subculture of metahuman society that the outside world knows nothing about.