Ryo Saeba works the streets of Tokyo as the City Hunter. He's a "sweeper" and with his sidekick Kaori Makimura, he keeps the city clean. People hire the City Hunter to solve their dangerous problems, which he does with a Colt Python. When Ryo's not working on a case, he's working on getting the ladies, and Kaori must keep him in check with her trusty 10 kg hammer.

When video creator Angie knocks on the door of the City Hunter detective agency looking for a missing cat, Ryo Saeba and Kaori Makimura think they have a simple case on their hands. But an attempt on Angie's life changes the game, leaving Ryo in the crosshairs of mysterious assassins on the trail of Angel Dust, a military technology capable of creating super soldiers. Under the watchful eye of his adoptive father Kaibara, Ryo will have to deal with a past he has tried to escape for too long.