Darksiders III is an action role-playing game in which the player returns to an apocalyptic Earth assuming the role of Fury, one of the Four Horsemen of the Apocalypse, in her quest to hunt down and dispose of the Seven Deadly Sins. From a behind view, she fights enemies using her whip and Hollow weapons acquired throughout the game.

The combat is no longer combo-focused with varied ground and aerial moves, rooms full of enemies and a hit counter. Instead, it is slower, grounded and methodical, focusing a lot on Fury's dodge and counters. Combat scenarios are not "gated" anymore, so the player can choose between eliminating enemies spread throughout the map, or simply passing them.

The leveling system and buffs are now a central part of the gameplay. Enemies drop Souls when they are killed, just as in the first Darksiders, but now the Souls are dropped every time the player dies. They then take the form of a glowing blue sphere which can be recovered by hitting it, and are placed somewhere near the point of of the last death. Souls are used as a form of currency, but are also an integral part of the leveling system. Upon reaching a checkpoint, the player can talk to Vulgrim and trade them for points to be spent in either health, damage, or arcane damage upgrades.

Weapons can be given perks by equipping them with Runes. These can be upgraded upon talking to Ulthane and providing him with the proper materials that can be collected by exploring different areas in the game.

The game's difficulty is scaled every time Fury defeats one of the Sins, and all enemies in the game are buffed to match her level.