Seduced by the power offered to him, a samurai allows harm to come to his infant son. The son, fated to destroy the 48 Fiends, has 48 body parts removed, one by each demon. The samurai sets the remains adrift along a river, where the still-living child is discovered by a kindly doctor. After raising the child, the doctor operates on him, replacing his missing parts with mechanical ones. Knowing the child's destiny, the doctor replaces his missing arms with sword arms, attaches a repeating rifle to one arm, and a cannon to one leg. The game begins with the now-adult Hyakkimaru beginning his quest to reclaim his body parts from the Fiends. Soon joined by the child-thief Dororo, the pair embark on a quest against ancient Japanese demons and the monsters they create.
Blood Will Tell is an action game where the player controls Hyakkimaru, a man whose body parts were stolen by demons when he was a child. His destiny is to reclaim each of his body parts, which allow him to increase his stats such as HP and power, as well as optional special functions (for example, the eye displays the game in colour, while the vocal chords allow him to speak). Hyakkimaru wields a sword, which can be used to attack enemies – he can also swap for his two smaller swords concealed within his arms. As he uses the swords, they level up and increase in power. Hyakkimaru can also charge up a sword attack, and if released at the correct time, is given the opportunity to enter a series of button presses for combos. If the enemy is killed during this combo, the player can perform a finishing move with the Triangle button which can yield bonus items ranging from health items to swords.
Hyakkimaru is also outfitted with a repeating rifle and a cannon in his leg. While these are very powerful, they both require their own ammo and cannot be used without it. The gun can be fired rapidly at foes, while the cannon must be charged and aimed for a powerful shot. Both of these weapons have the advantage of being long-range weapons, unlike his swords which must be used at close quarters.
At a certain point in the game, Hyakkimaru meets the child thief, Dororo. Dororo often assists Hyakkimaru during combat, and can be issued commands, such as 'fight', 'evade', 'collect items' or 'search'. Sometimes the pair will split up, and Dororo will be playable on his own. These sections are more puzzle-based, with the thief pulling switches to activate puzzles, dodging traps, and stealing items. Dororo can throw rocks from a distance, and later gets smoke bombs which are more incapacitating.