The renowned director of zombie movies, George A. Romero, made the original live-action commercials for Resident Evil 2. He was later supposed to direct the live-action Resident Evil movies, but the deal was given to Paul W.S. Anderson.

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.

Tofu from the secret game mode Tofu Survivor was originally created as a means to test the game's collision detection during development. He later got his own mode as a parody of HUNK's 4th Survivor.

There is an easter egg that allows you to shoot bullet holes in the screen anytime your character is facing the camera.