Originally, the female lead character was supposed to be Elza Walker. When Resident Evil 2 was made again, she was replaced by Claire Redfield. Elza's only appearance was in Resident Evil 1.5.

The S.T.A.R.S. office is way too small for a team of 12 and for some reason only has the desks of Barry, Chris, Jill, Rebecca and Wesker. They may have made some changes after the Mansion Incident but Brad's desk is missing and he had still been alive at the time the office was last used.

Normally, when the player searches the leftmost desk in the STARS office (which belongs to Albert Wesker), the player character will remark that the desk has been searched by someone else already. Should the player interact with it 50 times in a row, however, a roll of film can be obtained that, when developed, shows a photo of Rebecca Chambers from the previous game, wearing a basketball outfit. The picture is labelled "Recruit."

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 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.

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.