In the April 1998 issue of Electronic Gaming Monthly's spin-off magazine EGM2, the issue's Trick of the Month was an alleged method to unlock Akuma from the Street Fighter series as a secret playable character in Resident Evil 2. In order to unlock him, the magazine instructed players to play through both story scenarios six times each using only the Knife and the H&K VP70 gun on hand at the start of the game, and achieve an A ranking in all scenarios. Once these specific conditions are met, the player would receive some kind of clue that would lead them to the security computer in the Laboratory on Level B5F. At this point in either scenario, players would type "AKUMA" instead of "GUEST" into the computer, and after entering it would be sent to the Save screen and given the option to make a new save file with Akuma's name. After starting this new file, the game would start with Akuma breaking out of a cryogenic tank in an unused area where Tyrants were originally planned to escape from, and make his way through the game without the use of keys, with his main attack being a red Gohadoken used just like a gun by holding the Action button and firing.

In reality, after going through these difficult unlock conditions, entering AKUMA into the computer will not unlock anything, because the trick was an elaborate April Fools' prank (with the exception of the unused Tyrant area, that was real). This prank was the work of EGM2 editor and art director Mike Vallas, who took assets from Street Fighter EX and heavily modified and photoshopped them into Resident Evil 2 gameplay screenshots. It was one of two proposed April Fools' pranks that were in consideration to appear in the main EGM magazine that month, being beaten out by a prank trick for GoldenEye 007 where you could play as previous James Bond actors. Unlike Akuma, they actually were planned to appear in that game, but can only be accessed with GameShark codes.

According to a 1998 The Playstation magazine interview with the game's director Hideki Kamiya & writer Noboru Sugimura, they were asked about the chief of police character Brian Irons. Kamiya stated that he was originally going to be a normal police chief. His chubby exterior was still the same, but he would be seen properly wearing his uniform, talked like a normal officer, etc.

Sugimura credited himself as the one who made his deviant personality. Once they changed the police station building from a modern-day one to an old art museum, someone on the development team commented that it would be strange if there were medals just lying around in that place. Then Sugimura said "Well, we'll just have to make the police chief a weirdo then!", and Irons was what he came up with. He then created the character's hidden room, the idea that Chief Irons had been given bribes from Umbrella, and gave him "an insane grin on his face". Those who first saw the idea did not think it was very realistic, but Sugimura replied that "reality depends on persuasion and belief, so as long everything was consistent, it would appear real".

Kamiya stated that he was initially against turning Irons into a weirdo and protested it, but as the game's development progressed, the staff grew to like the idea and began coming up with "ridiculous details" to complement the personality shift. One example he cited are the hallway's torches leading to Irons' hidden room. The person who made it told him, "The Chief uses those to light a fire when he has his rituals!".

After confirming that Brian Irons' name appeared as a signature on the player select screen ID card in the first Resident Evil game, Kamiya revealed that wanted to use an "-ian" sound for both the first name and surname when coming up with the name, and decided that "Brian Irons" worked perfectly. He didn't think it would be anything more than just a lighthearted signature.

Sugimura commented that he didn't know that, and that when Resident Evil 2's development started the police chief was actually named Gordon until someone pointed out he was already given the name Brian Irons and stuck with it to connect it to the first game.

According to a 1998 The Playstation magazine interview with the game's director Hideki Kamiya & writer Noboru Sugimura, they originally had no intention of bringing back the Tyrant, since the first game already had him as the final boss.

Kamiya thought of making him a "perfect, invincible Tyrant", but after the two talked it over, they realized it was a bad idea because he would be so strong that the G-virus would be rendered meaningless, so they came up with the idea of the Tyrant's mission to retrieve the G-virus instead.

Sugimura also commented on about the Scenario choice for the Tyrant:

"One of the consequences of having players go through the same scenario twice was that, by the second time, they’re used to things and it’s too easy. For that reason we decided to have the Tyrant appear in Scenario B, as a way to raise the difficulty."

According to game's director Hideki Kamiya, the Umbrella Corporation can that gets stepped on at the start of the opening cutscene was supposed to have the Capcom logo on it, but when Capcom's management heard about it, they disapproved of the idea of their brand being stepped on, so the developers changed it to the Umbrella logo instead.

The PlayStation release was originally intended to be just a single CD game, however a last minute oversight with the size of the game's audio caused it to be shipped as a two-disc game. Though it could've been possible to reprogram the audio algorithms so it could all fit into a single 700 MB disc, as development was already behind schedule it was too late to do this, meaning higher manufacturing and shipping costs on an already tight budget.

The game's director, Hideki Kamiya, has attributed the decision and error to his youth and recklessness at that point in his career.

In an interview, Noboru Sugimura stated that Leon was originally supposed to start out in civilian attire. There would've been a scene between him and Marvin at the police station where he'd change into his police uniform.

"It’s true that with Racoon City destroyed, the police wouldn’t be actively on duty, so there’d be no real need for Leon to change into his uniform… but we wanted to show his determination to protect both the city and his principles by having him change into his uniform regardless. It was a scene with a lot of meaning. Unfortunately, due to a problem with the CG it got cut."

In the original PlayStation game, the Japanese version has a ranking system from S to D while the US version has a ranking system from A to E.

However, the US instruction manual incorrectly states that it is possible to get an S rank. This is because the US instruction manual is a direct translation of the Japanese one.

It is possible to spot the entrance gate to the Raccoon City Police Department that Jill uses in Resident Evil 3. In order to see it, the player must run up against the wall where it is hidden after killing all the zombies in the front plaza of the police station. Several zombies can be seen outside of the gate, though the player cannot interact with the gate itself.

According to early concept art Leon was supposed to own a bloodhound. Since this has not been mentioned in the series since, it is likely this was omitted from the canon.

In the police station on scenario 'A', the player meets character Marvin Branagh as he is resting on a locker. The name tag on that locker reads "JoJo". This is a reference to the anime "JoJo's Bizarre Adventure", or possibly a nod toward Capcom's JoJo's Bizarre Adventure (1998), which came out on the same year as Resident Evil 2 did.

A Tiger 99x electronic standalone handheld version of RE2 was released alongside the PlayStation release. It is basically a lite version of the Game.com version, also made by Tiger. Interestingly it is the first title in the series to feature a multiplayer function, two years before the arcade release of Survivor 2. This mode allows players to connect two of the systems with a connection cable and compete for a high score.

In the Japanese version, the death scene animations are censored by fading the screen to black, leaving only the sound effects and "YOU DIED" text.

At the beginning of scenario 'A', the player walks past a store named "Arukas", which is simply "Sakura" backwards. This is a reference to Sakura Kasugano, a character from the Street Fighter series.

Resident Evil 2 was originally supposed to have another surviving member of RPD found in the game named Roy, also called DJ. He is the only known concept character who was not renamed, redesigned or replaced but scrapped altogether.

The game's trial disc contains a number of unused voice clips. These include:
*Unused death screams for Leon and Claire
*A longer conversation between Marvin and Leon than what is in the final game in which Marvin begs Leon to shoot him in the head should he turn into a zombie.
*A clip of Ada saying "G-Virus..." in a more serious tone hinting at familiarity with the term.
*Leon shouting "Hold your fire!" in the parking lot when Ada shoots at him.

Getting to the Raccoon City Police Department on Normal Mode without picking up any items will spawn a special zombie wearing a yellow vest and camouflage pants in the department's back alley. This zombie is Brad Vickers, the helicopter pilot from the first Resident Evil.

Claire's default jacket has the same "Made in Heaven" logo as Chris's alternate outfit in the first game.

Resident Evil 2's story was continued in two now non-canon radio dramas exclusive to Japan called 'Chiisana Tōbōsha Sherry' (Sherry, the Little Runaway) and 'Ikiteita Onna Spy Ada' (Ada, the Female Spy, is Alive).

The S.T.A.R.S. group photo has an unidentified member on the far left. It is speculated that he is either the predecessor of Rebecca Chambers or an early concept of Kevin Dooley, an RPD pilot who sometimes helped the S.T.A.R.S. team on their missions. The latter would make sense as there is an RPD helicopter in the background.

Two of the characters in the game, gun shop owner Robert Kendo, and police officer Marvin Branagh, originally had much larger parts in Resident Evil 1.5, with Robert Kendo (Originally named "John") helping Elza Walker out and Marvin accompanying Leon and Ada throughout his story. At one point in 1.5, it appears that Marvin, rather than Sherry in the final game, is infected with a virus and the player has to get him a cure.

In the final game, both die fairly early on, and the player even has to kill a zombified Marvin in their character's "A" scenario.