Players control Hellboy in a third-person perspective as they progress through a series of levels broken up into six chapters. Levels consist of separate stages and routes occupied by multiple groups of enemies that differ between chapters. In most cases, all enemies in an area must be defeated in order to move to the next phase of the chapter, with ghostly barriers of smoke blocking paths while foes remain present. To combat opponents, Hellboy uses his stone "right hand of doom" for most hand-to-hand combat situations, with heavy and quick attacks that can be mixed together for varied combinations. Foes can eventually be stunned, as indicated with a grey flash. Hellboy also performs other attacks, such as slams and head butts, along with cinematic finishing moves when his opponent is near death. These finishing moves are necessary in the boss fights. As Hellboy defeats his enemies, he receives energy that is stored in his health meter. This energy is used to execute certain grapple moves and to activate "Hellmode", where Hellboy's right hand of doom becomes engulfed in flames causing further damage in combat.
Another weapon that can be used is Hellboy's oversized pistol known as the Samaritan. The weapon fires single shots with up to nine different types of ammunition (certain types are not available on certain levels). While most kinds are for damaging opponents like "Heavy", "Grenade" and "Splinter" ammunition, others can be used during the game's puzzles like "Ignite" to light beacons or "Release" to destroy cursed vines. Additional types of ammunition like "Charge" can only be obtained by defeating certain enemies with a finishing move.
Hellboy can pick up various objects on each level to be used as a projectile or weapon such as barrels, hammers, pipes, rocks and even parts of enemies or their own weapons. Some items are used in tasks to progress through levels such as lighting fires or lanterns. Other puzzle elements include certain obstacles like doors and cracked walls that require Hellboy to smash through with his right hand of doom and then pull levers connected to obstructions. Throughout the single player mode, there are collectables in the form of artifacts and lores. These act as additional small details to the story and increase maximum energy capacity for the Hellmode ability.
The story mode can be played cooperatively with another player, both locally with another controller or online over Xbox Live for the Xbox 360 version and PlayStation Network for the PlayStation 3 version. The game's host always plays as Hellboy and can save each chapter while the second player has the choice of playing as either Abe Sapien or Liz Sherman, both with their own unique abilities and form of combat such as Abe's array of martial arts moves for combat or Liz's pyrokinesis.