Devil May Cry started out as Resident Evil 4. Producer Shinji Mikami felt it strayed too far from the series' survival horror roots and gradually convinced all the staff members to make it an independent game. The story was eventually rewrote to be set in a world full of demons and the hero's name was changed to Dante.

After the abandoned house scene where Leon is knocked out by Chief Mendez, he awakens without his jacket without explanation. In "Separate Ways"' second chapter, Ada comes across a Ganado wearing Leon's jacket.

Should the player repeatedly shoot the lake just before battling Del Lago, the monster will burst out of the lake and eat Leon in one gulp, killing him instantly. The HD and Steam editions of the game award the player with the trophy/achievement "Don't Shoot The Water!" for doing this.

Robert Kendo's brother, Joe Kendo, is hinted to still be alive, as the words "Kendo Custom Shop" have been engraved in Leon's gun, the Silver Ghost.

After the Credits of Resident Evil 4, in the "copyrights" section, it says "This game is protected under the laws of Raccoon Police Department. Unauthorized duplication, distribution or exhibition may result in civil liability and criminal prosecution by an appropriate S.T.A.R.S. member. And then some."

Leon was originally supposed to be rescuing Sherry Birkin in RE4 and the story was supposed to tie in with what Wesker said in Wesker's Report: "Sherry is safe in our hands". That part was, however, removed from both the game and the 10th anniversary edition of Wesker's Report.

There is an early build of Resident Evil 4 that was completely scrapped, now referred to as Resident Evil 3.5. In the trailers and gameplay footage released for the game, Leon battled possessed dolls, a fog monster that resembles Uroboros, and a recurring enemy called Hookman.

Some elements used in Resident Evil 3.5 include Quick Time Events, some sort of secondary weapon for fighting the dolls, and a blue screen filter for battle sequences.

The unlockable Matilda pistol is actually the customised Heckler & Koch VP70 handgun Leon used in Resident Evil 2. Leon could find a stock and attachment for his VP70 pistol in RE2 that allowed him to fire bursts.

There are a few possible references to the 1994 film "The Professional", starring Jean Reno. Jean's character's name in the film was "Leon", an unlockable pistol in RE4 is called "Matilda", after the 12 year old female protagonist of the film, and Resident Evil 4's hardest difficulty setting is named "Professional."

Most of the usable guns in the game are real life guns under a nickname.

Default "Silver Ghost handgun" = H&K USP/S&W Sigma/Ruger P85 hybrid
Punisher = FN Five-seveN
Red9 = Mauser C96 (Red9 was an actual nickname for Mauser variants that handled 9mm bullets)
Blacktail = Springfield Armory XD
Matilda = Heckler & Koch VP70M (The very same pistol that Leon used in RE2, with its stock attachment and burst fire mode active)

Shotgun = Remington 870
Riot Gun = customised Benelli M3 Super 90
Striker = Armsel Protecta ("Striker" was the gun's original production name)
Ada's Shotgun = Mossberg 500

Rifle = Springfield M19031A1
Semi-auto Rifle = Heckler & Koch SL8

Broken Butterfly = S&W Schofield Model 3/Colt Single Action Army hybrid
Killer 7 = Colt M1911 magnum variant with an AMT Hardballer-style laser sight
Handcannon = Smith & Wesson Model 500

TMP = Steyr TMP. HUNK uses a customised variant resembling the Brugger & Thornet MP-9
Chicago Typewriter = Thompson submachine gun. Leon normally uses the M1A1 Army service variant while Ada and Mobster outfit Leon use the famous 1921 drum magazine version. "Chicago Typewriter" was one of many famous real life nicknames for the Thompson.

Rocket Launcher = RPG-7

The only truly fictional weapons are the Plaga Removal Laser 412, the Mine Thrower and the Bowgun.

Before the events of the game, the villagers had their own children. According to the Biohazard 4: Incubate DVD, there were no children in the game because they were killed by the Plaga Virus.

The gun Killer7 is a reference to a game by the same name, produced by Shinji Mikami and published by Capcom. A character in Killer7 used a similar looking gun.

Trying to reload the Chicago Typewriter (which has infinite ammo by default) while wearing the Leon's Mobster Outfit instead triggers a small taunt wherein he adjusts his hat and scoffs. If the player reloads 4 times in a row, a more dynamic animation will play of Leon tossing and catching his hat.

During the standoff with the Ganados in the cabin, shooting Luis enough times will trigger a cutscene where he will shoot and kill Leon, resulting in a game over.

When the player attempts to look up Ashley's skirt she will exclaim "UGH! You PERVERT!" Or "HEY! What are you looking at!" and cover herself. Humourously, this will trigger if Leon's head ends up directly under her skirt in any situation including if he is knocked down by enemies.

If Ashley is wearing any of her alternate costumes, this animation will not trigger.

The title menu for Ada's Separate Ways Campaign was likely inspired by the movie poster for La Femme Nikita.

The gun Broken Butterfly has a description which references the film Sudden Impact. In the movie, a character says "Go ahead, make my day" while holding a revolver. The description for the Broken Butterfly reads: "This will make anyone's day."

Nuby Tech, a gaming peripheral company, created a chainsaw-shaped controller inspired by the Chainsaw Man enemy in Resident Evil 4. Separate versions were made for the GameCube and PS2. However, it didn't enhance the playing experience, and was criticized for its poor button layout.

During the segment of the game when playing as Ashley, it is possible to open a door into a Zealot to stun them and then perform Leon's suplex move on them. This glitch is only present in the GameCube version of the game, and was edited out in all other versions.

Any instances of decapitation were strictly removed from the Japanese release.