Resistance: Retribution takes place weeks after the events of the PS3 title Resistance: Fall of Man. The player is James Grayson, a former British Marine. Grayson finds his brother infected by the Chimera virus and goes on to destroy every conversion centre he can find. The Maquis enlist Grayson, and it's his job to retake Europe from the Chimera. The game is presented as a third-person shooter and makes use of a cover system that allows the player to hide behind objects. While hiding from Chimera, Grayson is able to pop out quickly and attack the enemy. Covers are locked automatically when Grayson goes near them and aiming assistance is also provided.

Players who own a copy of Resistance 2 and play Resistance: Retribution on a PSP 2000 or 3000 can connect the AV output to a television to play the game with a DualShock 3 controller. Also when owning both games, they can be linked using a USB cable to open up the Infected mode. It provides an alternate history, mixing events of the two games. Grayson is recruited by Specter Lieutenant David LaSalle (from Resistance 2) and is infected with a mutated version of the Chimeran virus. In this game mode, Grayson wears a Specter uniform and has glowing Chimeran eyes. He can regenerate health, gets access to new weapons and breathes underwater. He is also able to reach hidden passages and pick up intel, unlocking plasma grenades and even a further expanded story. This game mode ends when the game is quit and progress cannot be saved.

Multiplayer consists of battles through Ad Hoc and Infrastructure with statistics tracking on MyResistance.net. The included game modes are deathmatch, team deathmatch, containment, capture the flag and assimilation.