Resident Evil 4: Wii Edition includes the bonus content from the PlayStation 2 version and introduces several changes to accommodate the Wii Remote's motion controls. The aiming system features a larger reticle that changes from green to red when targeting an enemy, replacing the original narrow laser sight. A “quick knife” command is added, allowing automatic targeting of the nearest enemy or object, and motion-sensitive quick-time events supplement traditional button prompts.

Visually, the game is comparable to the original GameCube version and generally improves upon the lower-resolution graphics of the PlayStation 2 release. However, a few graphical elements—such as low-detail herb models—appear to be carried over from the PS2 version. The Wii Edition also supports the classic controller, restoring traditional controls and the original laser sight aiming. Additional differences include a lower overall difficulty and slightly faster animations for Leon’s actions.