Los Ganados can dodge, wield melee and projectile weapons, and are capable of working collectively and communicating with each other. The main enemies are violent villagers referred to as Los Ganados ('The Cattle' in Spanish).

These are often incorporated into the game's many boss fights, in which the player must avoid instant-kill attacks. There are also quick time events, in which the player must press buttons indicated on-screen to execute actions such as dodging a falling boulder or wrestling an enemy to stay alive. Based on the situation, players can interact with the environment: kicking down a ladder, jumping out of a window, dodging an attack or executing a 'finishing move' on weakened enemies. Resident Evil 4 adds context-sensitive controls. Players can shoot down projectiles like thrown axes or scythes. For example, shots to the feet can cause enemies to stumble, and shots to the arms can make them drop their weapons. Unlike previous games where players can only shoot straight, up or down, players have more options. There is no crosshair for firearms, instead, every firearm has a laser sight.

The camera is placed behind Leon and zooms in for an over-the-shoulder view when aiming a weapon, or a first-person view when aiming with a sniper rifle. The gameplay focuses on action and shootouts with fewer survival horror elements. Kennedy, from a third-person perspective. Departing significantly from the series' previous games, the player controls the protagonist, Leon S.

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