A massive anomaly ravaged Japan's mainland and destroyed most of Tokyo, sinking three-quarters of the city into the ocean.
Ten years later, the story shifts to Ganta Igarashi, a seemingly ordinary student attending Nagano Prefecture's middle school. As an escapee, a survivor of the great earthquake, Ganta has no memories of the tragedy and has lived a normal life. This all changes when a strange person covered in blood and crimson armor floats through his classroom windows. Grinning madly, the 'Red Man' massacres Ganta's entire class but instead of killing him, embeds a red crystal shard in Ganta's chest. Within days of the massacre, Ganta is subjected to a kangaroo court as a suspect and is sentenced to death at Deadman Wonderland, a prison that doubles as a theme park.
Arriving at the prison, Ganta is fitted with a special collar which monitors his location and vital signs. A lethal poison is constantly injected into his bloodstream through the collar, but it can be neutralized by consuming a peculiar candy-like medicine every three days, which can be acquired through various activities in the prison, i.e. performing for audiences, working backstage, purchasing with Cast Points (a form of currency among inmates at Deadman Wonderland), etc. To gather Cast Points, an inmate must perform in the facility's lethal games and survive. Fortunately for Ganta, he is aided by a mysterious girl named Shiro who apparently knows Ganta but whose existence is unknown to the other prisoners.
While trying to survive as an inmate on death row, Ganta intends to find the 'Red Man' to clear his name. In a bizarre twist, Ganta begins to develop the ability to manipulate his own blood, to the point of turning it into a weapon. Unknown to Ganta, he has become one of the prison's "Deadmen," an isolated group of prisoners possessing the Branches of Sin an ability which makes them capable of controlling their blood. After his ability is discovered, Ganta is forced to participate in brutal gladiatorial death matches known as Carnival Corpse, whose anonymous spectators pay large amounts of money to watch. In his long struggle to survive he manages to befriend some of those he fought off in the arena and with their help, Ganta continues his quest to uncover the identity of the 'Red Man', why he turned into a Deadman, and the dark secrets the prison authorities are hiding.