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.

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. The first scrapped version would have featured a character called Tony Redgrave, the son of Ozwell Spencer mentioned in Resident Evil (1996) and Resident Evil (2002), who gets superpowers from being infected with the G-virus. However, producer Shinji Mikami felt that the concept strayed too far from the series' survival horror roots. This version eventually became its own game (and franchise), titled Devil May Cry (2001), with Tony changed to Dante.

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 Matilda handgun was named after the character with the same name from the movie Léon: The Professional (1994), which also had a main character called Leon.

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.

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 quitting one's job). However, due to the Gamecube version'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, but approved of the addition of additional missions on these versions. 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 shown a remarkable longevity, having also been ported to the Wii, and remastered for the Xbox 360 and PlayStation 3. It was then updated again for a PC re-release which later became the basis for HD ports to the Xbox One, PlayStation 4, and finally the Nintendo Switch. Simplified versions were also created for the iPhone and iPad.

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, produced by Shinji Mikami. This was the first version to feature Leon from Resident Evil 2 (1998), sporting a variation of his current costume and fighting a mist-like virus. The second shown version had one bad guy in particular that sported a hook on one of its hands, and the final logo for the game still reflects this. A third version was created but never unveiled to the public; it contained the classic zombies again, but it was canceled after a few months, before Mikami took over as director and transformed the title into its final version. In Japan, an exclusive DVD bonus disc included with the game had footage from the second version that was made.

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 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".

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.

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 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.

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.

The game features a dynamic difficulty, meaning that the game adapts the strength, stamina and even number of the enemies depending on how well or badly the player is doing.

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.

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. Another glitch caused Leon to move much faster than normal, making shooting and slicing a knife much easier.

Strangely, there are no children seen among the villagers in the game. Originally there would be, but due to strict rules concerning the depiction of violence targeted at children in video games, the developers decided not to include them. Although not addressed within the game, the official explanation is that children cannot survive the Las Plagas infection, so they have all long died before Leon arrives at the village.

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

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

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

During the main game's end credits, pictures are shown of the villagers before and during a Las Plagas infection. Apparently, these pictures come from a book that Ada Wong can be seen holding in the house of Bitores Mendez, in the beginning of Mission 2 of her 'Separate Ways' game.

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

Two different versions were made for the PC. The first version was based on the PlayStation 2 version and published by Ubisoft in 2007. It was widely criticised for the lack of mouse control, missing lighting in certain parts and the low texture resolution, which made it inferior to the PlayStation, Wii and Gamecube version. A vastly improved second port, which was based on the HD versions for the PlayStation 3/Xbox 360, was published by Capcom in 2014.

The second Gamecube version of the game was called the 'Hallucination version' or 'Hook Man version'. It featured Leon Kennedy entering a haunted castle looking for Sherry Birkin from Resident Evil 2 (1998), where dolls and other objects come to life and he has to fight an enemy called the Hook Man. Many of the elements of this version ended up in the final game, such as: the over-the-shoulder camera perspective, laser-sight aiming, suits of armor attacking, the struggle-free animation, and an on-screen health indicator; Sherry Birkin was changed into Ashley Graham.

The music heard during chapter 2.2 as Leon and Ashley try to escape the rural village at night may be familiar to those who have played Resident Evil: Code: Veronica (2000); it is the same music heard when Claire Redfield enters the torture basement behind the guillotine at the prison facility.

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

Concept art reveals several types of enemies that didn't make it into the finished game. These include: the 'Electric man' (resembling a Regenerator but no explanation as to what it does); the Parasite Woman (a women in a straitjacket wielding a large mutated arm); and the Lurching Man (a prototype Regenerator design that can alternate between a solid and liquid form).

The first Gamecube version with Leon Kennedy was dubbed the 'Castle version' or 'Fog version', and had Oswell E. Spencer (the unseen 'man behind the curtain' from Resident Evil (1996) and Resident Evil (2002)) as the main villain. It featured Albert Wesker attacking Spencer's castle with a new virus, which also infects Leon as he explores it, giving him superpowers in his left arm. Leon would later be accompanied by a young imprisoned girl and her BOW attack dog, and they would eventually discover the origins of the T-virus. Another part of the game would take place on an airship. This version was canceled because the main enemy would have been a black fog that proved too difficult to animate. The female partner and her dog would become a separate game, Haunting Ground (2005), and many of the other elements finally ended up in Resident Evil 5 (2009).

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).

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").

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

Unusual for a horror game at the time, this one was released uncensored in Germany, where it obtained an 18 rating. However, because Capcom didn't obtain a rating for the game modes "Assignment Ada" and "The Mercenaries", those modes were excluded from the German version. The complete version of the game that contains all modes was therefore banned in Germany in 2005 (the ban was lifted in 2016). After the release of the German Gamecube version, Capcom later noticed that both modes were required in order for the player to unlock the Handcannon and the Chicago Typewriter. When the Wii version was about to be released in Germany, Capcom modified the game to make it possible for the player to unlock both weapons once the Professional mode was completed.

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).

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.

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.

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 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.

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.

Hidden death: if you hit Luis five times during the Ganados ambush in the cabin in chapter 2.2, he will shoot and kill you.

Albert Wesker, long-time nemesis in the Resident Evil series, is only mentioned in the main game as the mastermind behind Krauser's and Ada's involvement in obtaining a Las Plagas sample. He makes a visual appearance in the 'Separate Ways' side-missions, though.

When Ada and Leon meet up in Salazar's quarters, Ada sneaks up from behind and (after a brief fight) tells him: "Long time no see". Albert Wesker says the same thing when he approaches Chris Redfield from behind in Resident Evil: Code: Veronica (2000).