Picking up six years after Resident Evil 2, the fourth game in the series follows a former cop (now US agent), Leon S. Kennedy, to Europe on a top-secret mission to investigate the disappearance of the president's daughter Ashley. As Leon encounters unimaginable horrors, he must find out who or what is behind everything. Old friends...and enemies...lurk around every corner as Leon attempts to find out who is truly behind the kidnapping of the president's daughter.

Resident Evil 4 is a major change from the previous installments. Instead of a fixed third-person perspective, the game features a new "behind the back" movement camera angle and an "over the shoulder" aiming feature that allows players to control their gun movement for specific body part hits. It features a brand new AI system and more open environments that allow enemies to work together to capture and corner Leon. Enemies are now humans, which allows them to climb up ladders, open doors, and use weapons throughout the game.

The entire item system has also been revamped, so that smaller items no longer require an entire item space to hold. Instead, items take up blocks of space in a briefcase according to their real-life size, to allow for many more items and weapons. Leon can collect treasure from enemies or from the surrounding area, and visit the infamous "merchant" to purchase bigger briefcases, treasure maps, weapons upgrades, and powerful weapons such as the one-shot RPG.

There is also the Mercenaries mode from Resident Evil 3, which allows the player to play survival scenarios as characters such as Hunk and even Albert Wesker himself.

Unlike the original GameCube release, later released platforms come with a bonus story mode called Separate Ways which becomes unlocked after finishing the main game. This story lets you play as Ada Wong and occurs in parallel to the main story, showing you what Ada did, who she contacted, and where she's been when she wasn't with Leon. While most of the locations and weapons are the same, there are some entirely new levels and Ada's personal gadgets not previously seen in the main story.