According to a 2018 Rely on Horror interview with the game's producer Yoshiaki Hirabayashi, they decided to streamline the game's narrative by merging the A and B scenarios when playing as Leon or Claire in the original game (which was four scenarios total played in a dual perspective) into a single, cohesive story for each character. This was meant to remove the repetition from that approach while ensuring that players can still enjoy the depth and intensity of the narrative without having to play through multiple scenarios to see everything.

In a 2018 VG247 interview with the game's producer Yoshiaki Hirabayashi, he revealed that the approach to audio and music in the game focused on trying to create immersion in a third-person perspective during combat with zombies through carefully designed audio elements. This is in contrast to the approach taken in Resident Evil 7: Biohazard, where the first-person perspective required a focus on environmental sounds to build tension and immersion by using real-world audio cues and sometimes muting them to increase suspense. He also commented that they tried to ensure the audio remained true to the original game's vision by bringing on the original composer, Shusamu Uchiyama.

In the West Offices of the RPD Station there is a locker with the name JoJo on it. This is a reference to the manga and anime series JoJo's Bizarre Adventure and appeared in the original Resident Evil 2 as well.

In the West Offices of the RPD Station there is a desk with a nameplate that says "Rita Phillips." This is a reference to Resident Evil Outbreak: File 2, where Rita was one of the last survivors who managed to escape the police station before Leon and Claire's arrival.

The license plate on Claire's motorcycle, "J2198", is a nod to Resident Evil 2's original release date, January 21st 1998.

The scene where Elliot Edward gets attacked by zombies is censored in the Japanese release. In the international version he loses his lower body and guts and entrails are visible, whereas in the Japanese release he still has his legs intact. Even in the CERO Z version of the game (the version with the highest possible rating) his death is still censored.