The story is set in the year 2011 in Neo-Kabukicho, a fictitious version of the real red-light district of Shinjuku, Tokyo. A wave of violent crime is being caused by a new contact lens drug called "Skull Eyes", enabling people to become superhumans called Kabukimono. It follows the story of the reincarnated Lion-Maru and Tiger Joe from the original Kaiketsu Lion-Maru.