Darksiders has players take on the role of War, one of the Four Horsemen of the Apocalypse, who has been tricked into bringing about a war between heaven and hell, resulting in heaven's defeat and the Earth's enslavement. Now stripped of his powers by the Charred Council, he must go to Earth and punish those responsible for deceiving him and causing the enslavement of Earth. As well as having to fight hell's minions, War has to contend with a group of vengeful angels that are bent on bringing him to justice. That way, not every important demon met in the game has to be defeated. War can make alliances with some of them when there are mutual interests.

The game has third-person hack-and-slash gameplay with a large variety in weapons and combos. These can be leveled up and are expanded with enhancements that provide active and passive abilities. Other actions include dodging, blocking, finishing off enemies with a special move, double jumping and gliding using wings, climbing ledges, throwing objects in the environment, and a mix of ranged-weapon and melee attacks. Defeating enemies provides blue souls. These can be exchanged with the demon Vulgrim at certain locations to acquire new attacks and items. Another important means of attack is Wrath. Enemies leave behind yellow clouds of this material and it is used to fill up a meter to perform special actions. Much of the game is spent fighting along with typical platform puzzle elements.

There are also sections with very different gameplay: flying in the air, fighting on horseback, and shooting angels out of the sky with a Redeemer ranged weapon. Levels are fairly linear, but all locations can be revisited afterwards later in the game through Serpent Holes. As War acquires new weapons and new means of attack, previously explored locations' walls of crystals can be shattered to find new items. During the game War gains the ability to fill a Chaos meter and change into his Chaos Form. He transforms into a large demon and can easily take out large groups of strong enemies for a short time.

The game encourages focused surveillance of the environment to retrieve hidden objects and chests, and many collectibles. Some of these are used to extend the health or Wrath meter, while others can lead to the forging of a very strong armor.