Vanquish is a third-person shooter with a focus on cover tactics, similar to Gears of War, but it is also the first game with those mechanics by a Japanese development team. The player controls Sam Gideon, a member of DARPA, who fights with the new ARS (Augmented Reaction Suit) system battle-suit, which grants him incredibly fast reflexes and maneuverability, inspired by the 1970s anime television series Casshern. The story takes place in the future. The Order of the Russian Star, after taking control of Russian government with a coup d'etat, hijacks an American space station dedicated to the creation of solar energy and uses it to destroy San Francisco thus declaring war to the United States. They demand an unconditional surrender or they will also destroy New York city. Gideon is sent there to stop them. During the game Gideon works together with a military task force, led by Robert Burns. The military unit is controlled by the computer AI. They provide support and Gideon can revive them when they die. Gideon is helped from a distance by Elena Ivanova, who tracks the suit and provides information about the environment.

Gideon's suit provides for very fast-paced gameplay. He is able to boost slide to new areas that provide cover and there is a very strong melee attack. The focus is however on ranged-weapon shooting. Some of the fights are also shown as in-game cinematics showing off elements of the suit's power (such as flying) that are not available to the player. Health is restored automatically, but when too much damage is taken, the game goes into an Augmented Reality (AR) mode where all the action is slowed down, similar to bullet time. During that short time frame, more precise firing is possible and there is some time to look for cover, but health is at a critical state. AR can also be triggered manually, but this drains the suit's power. Sliding also drains it, so Gideon often needs to find a safe place to restore the suit before it overheats.

Weapons include an assault rifle, heavy machine gun, disk launcher, lock-on laser, sniper rifle, rocket launcher and LFE gun. There are also regular and EMP grenades. All weapons have a limited amount of ammo, but there are many pods where new ammo can be found or a weapon can be exchanged. A maximum of four weapons can be held at all times. Players are encouraged to hold on to weapons, as they can be upgraded, with more damage or larger storage for ammo. Stationary turrets can also be taken over. Almost all of the opposition consists of robots or mechanized organisms. Next to regular enemies, there are larger bosses with highlighted weak points that need to be targeted. Regular enemies sometimes have these too, usually on their back, and targeting those kills them quicker. During the larger fights there are sometimes minor Quick Time Events.

The game is split up into five chapters with about seven acts each, and cut-scenes further the story. Most of the missions require constant moving and dodging to stay alive. There is also a single sneak mission and a few on-rails segments with a vehicle.