Resident Evil 4 was in production for many years due to the constant changes it went through. The game was scrapped and started again four times. One of the scrapped versions though eventually became its own game (and franchise), titled Devil May Cry (2001).

The story is supposed to take place in Spain, but the Spanish spoken by the village people is the Mexican dialect (which has a very different pronunciation). Furthermore, the currency used throughout the game is the Peseta, which is curious since Spain had switched to Euros in 2001, but this may have been done to show how behind the times the area is compared to modern Spain.

The Matilda handgun was named after the character with the same name from the movie Léon: The Professional (1994).

This is the first Resident Evil game where Umbrella isn't responsible for the monsters and bio organic weapons (BOW) creations. Umbrella is gone by this point, and may yet come back.

Ashley will cover her skirt and yell, 'Oh, you pervert!' if the player aims upwards towards her while on lower ground.

This Resident Evil used all new enemies that were not in any of the previous games. No zombies, no Cerberus, no crows, no giant spiders, no tyrants, no hunters, no lickers made it to this installment.

The earliest version of the game was announced for the PlayStation 2 under Resident Evil 2 (1998) (Resident Evil 2) director Hideki Kamiya. This build was eventually canceled as a Resident Evil installment, and became the title known as Devil May Cry (2001). Eventually, development was moved to the GameCube console and another build emerged. This was the first version to feature Leon from RE2. The first version shown had Leon sporting a variation of his current costume and fighting a mist-like virus. The second shown version's showed one bad guy in particular that sported a hook on one of its hands, and the logo for the game reflected this (this can still be seen in the final logo). One more version was created and canceled before Shinji Mikami took over and transformed the title into what it is today. Of all the builds developed, only one of them was never unveiled to the public; it was the one that was being worked on right before Mikami took over, and it contained the classic zombies again. In Japan, an exclusive DVD bonus disc included with the game has footage from the second version that was made.

Resident Evil 4 was originally said to be part of an exclusivity deal between Capcom and Nintendo, but the situation was more complicated than that. As a ploy to attract older gamers with more mature games, Nintendo made an agreement with series creator and Capcom designer Shinji Mikami to develop three Resident Evil titles exclusively for the GameCube. These three games were Resident Evil (2002), Resident Evil Zero (2002), and Resident Evil 4. Mikami had lost trust in the technical capabilities of the other consoles, and famously stated that if Resident Evil 4 came out on another platform, he would "cut off his own head" (a Japanese slang for someone quitting a job). However, due to Resident Evil 4's immense popularity but disappointing sales, Capcom decided to port it to the PlayStation 2 and PC as well. Since Capcom and Mikami had made separate deals with Nintendo, Capcom claimed that Resident Evil 4 wasn't part of their full exclusivity deal with Nintendo. Mikami would later apologize for the game becoming multiplatform despite his earlier promise. Capcom and Nintendo later negotiated a deal where Capcom would port Resident Evil 2 and 3 exclusively to the GameCube for the remainder of the 6th console generation. Resident Evil 4 has since been ported to the Wii, and has been remastered for the Xbox 360 and PlayStation 3. It was then updated again for a PC re-release which later became the basis for ports to the Xbox One and PlayStation 4.

The Killer 7 handgun was named after Killer7 (2005), another Capcom game produced by Shinji Mikami. This is the only weapon in the game not to feature an exclusive upgrade.

The hallway sequence where the player has to dodge lasers via quick time events, is likely a reference to the Resident Evil (2002) movie, where the film's characters encounter almost the exact same situation.

This is the first Resident Evil presented in 16:9 widescreen. All previous entries were displayed in 4:3 fullscreen. This is why when the game is played on an 4:3 television it appears to be letterboxed.

The original GameCube version contains a unique glitch where sometimes after reopening a save file, Leon will move sideways instead of forward. If you reset the game and reopen the save file though, Leon will walk straight again.

The last Resident Evil entry directed by series creator Shinji Mikami. He was not involved in the next game, Resident Evil 5 (2009), stating that "it was not the game he would have made".

In addition to the Mathilda, the game pays home to the movie Léon: The Professional (1994) in an unlockable "Professional" difficulty.

An HD remaster of Resident Evil 4 was released for the XBox 360 and PlayStation 3 in 2011. An Xbox One and PlayStation 4 remaster was announced on February 25th, 2016, and was released on August 30th of the same year. This remaster ended up just being a port of the PC's Ultimate HD Edition to consoles. The PlayStation 4 and Xbox One versions render in 1080p at 60 frames per second, features the updated textures and character models from the PC's Ultimate HD Edition, and include all bonus content from all previous versions of the game. There is no option to use the original GameCube assets though, unlike the PC's Ultimate HD Edition. This version was finally released on the Nintendo Switch in 2019 as well, without the Switch motion control function, though.

During any cutscene in which Leon draws his weapon it will always be the handgun that you start the game with that he draws,even if you've sold it and bought a different one.

The gameplay was changed after Mikami realized that many of the game designers were tired of the same formula used in other Resident Evil games.

This is the first Resident Evil game to feature Pro Logic II surround sound.

Saw two different releases on the PC.

The backstory between Leon Kennedy and Jack Krauser is partially explored in Resident Evil: The Darkside Chronicles (2009).

Named 2005 Game Of The Year by G4TV (defunct ) & Gameinformer.

The cult name Los Illuminados translates to "The Enlighted" in English.

A fan game was being developed by a Resident Evil fan who goes by the name ShiguWorks, the project was called "Resident Evil CODE: Madman", which recreated the canceled "Castle" and "Hookman" versions of Resident Evil 4 (2005).

The parasites, Las Plagas, translates to "the plagues" in English.

Those infected and controlled by Las Plagas are called Ganados. In Spanish, "ganado" means "cattle" or "livestock". However, it is rarely used in the plural (except as a form of the verb "ganar", which means "to win" or "to earn").

During the end boss battle, Ada Wong suddenly appears and throws a special rocket launcher that can be used to kill the boss. The same thing happens at the end of Resident Evil 2 (1998).

Hidden cutscene: before the battle with the lake monster, if Leon shoots at the water from the pontoon, the monster will come out of the water and eat him.

If you save the dog from the bear trap at the beginning of the game, it will come back to help you during the fight against El Gigante.

At the start of episode 1-3, after Leon's second encounter with the bearded chief Mendez, if the player chooses to go back in the bedroom to follow him, it will trigger a hidden cutscene. The chief violently attacks Leon, but he is rescued in time by an unidentified Ada Wong. The same cutscene appears in Ada's 'Separate Ways' side-mission.

After the fight with the lake monster, there is a short hidden cutscene with wolves if the player goes back to the entrance of the area. If the player follows the normal path, wolves are not encountered until Leon gets back to the church.

The first port of the game for the PlayStation 2 contained an additional campaign called 'Separate Ways', in which the perspective of Ada Wong is followed in parallel with the events of the main game. This side-mission has made it to all subsequent ports, re-masters and re-releases, and explains several plot points in the normal game: e.g. how Ada rang the church bells that drew away the villagers from Leon in the beginning, and how she rushed to come to his aid several times despite orders to kill him. Also, Leon's coat that disappears after he is first taken prisoner can later be seen worn by a villager in this scenario.

The confrontation with Verdugo (Salazar's 'Right Hand') is the only boss fight in the game that can be partially skipped. The player will need to fight or avoid him until the elevator is activated, and can leave afterwards; Verdugo will not follow below. However, if Leon returns to the area, Verdugo will still be waiting for him.