The design for Castle Dimitrescu was likely influenced by Peles Castle, which is found in Transylvania, Romania.

During a livestream hosted by voice actresses Maggie Robinson and Nicole Tompkins, who both voice Daniela and Lady Dimitrescu respectively, they requested the game's modding community to make a flower crown for Cassandra Dimitrescu's character model as a commemoration to the character's voice actress Jeanette Maus, who passed away from colon cancer before the game's release.

There were plans to include Ada Wong in the game where she would have saved Ethan from Mother Miranda and her followers shortly after Ethan is captured by Heisenberg after entering Castle Dimitrescu for the first time. However, Ada's role was cut from the game due to conflicting scenarios.

In May 2021, Richard Raaphorst who directed the 2013 film "Frankenstein's Army" accused Capcom of plagiarism, because the boss enemy Sturm looks almost identical to one of the monsters in the film.

In a cutscene, before you play as Chris Redfield, he's seen smoking a cigarette inside his car. This is a reference to Resident Evil (1996), where Chris can be seen smoking a cigarette in both the live-action character introductions and Chris' bad ending in the uncensored version of the game.

When obtaining the M1911, the improved grip upgrade has a golden bee emblem on it. This is likely a reference to the 'Lure of Bee' key item from Resident Evil (2002).

During the scene where Ethan sees Spoiler:Eveline from Resident Evil VII: Biohazard in a desolate, snowy part of the village there is a partially modelled version of the interior of Ethan's house far below the geometry of the area, suggesting that it was originally going to be part of the scene, but ended up being used differently in the final game.

The skybox used throughout the whole game (including in Ethan's house and in the village) that cannot be seen during normal gameplay is a street view of Kensington Gardens, one of London's eight Royal Parks which were originally used exclusively by the British royal family, but today are now open to the public.

If Daniella is killed before Cassandra, an event between Lady Dimitrescu and Cassandra will play out in the main hall, where she demands that Cassandra searches for Ethan. If Cassandra is killed before Daniella, a different event will play out with Dimitrescu calling for Cassandra, realizing she is dead, and angrily yelling to Ethan, before storming to the dining room. Shooting at Dimitrescu to catch her attention before she leaves will prompt her to turn and attack Ethan saying "The entire bloodline of House Dimitrescu is done in? By the likes of you!?"

When activating the Duke's shop, there is a chance the Duke might quote the Merchant from Resident Evil 4 and say the latter's line "whatta ya buyin'?" and then follow it with a mention that the Merchant is a friend of the Duke's. Additionally, the developers stated that the Merchant was their primary basis for the Duke, furthering the connection between the two venders.

The game takes place over the course of a day. Whenever Ethan obtains a flask containing a piece of his daughter, the sky changes to reflect the passing of time. This is also reflected in the main menu of the game where the color and light of the sky is reflected by the current time of day of the last saved file.

At the start of the 2nd phase of Karl Heisenberg's boss fight, his factory is detonated by Chris Redfield in the background and while this happens he says: "I'm going to murder that boulder-punching asshole, but you're first."
This is a reference to a quick-time event from Resident Evil 5 where Chris Redfield has to punch a boulder several times in rapid succession to move it and progress through the final boss fight.

Within the game's demo, a bottle of cleaning fluid can be found in one of the homes with writing on the label. Looking closely reveals that it quotes the first verse of the 1992 song "Creep" by English alternative rock band Radiohead.

Actress Jeanette Maus, who voiced one of Lady Dimitrescu’s daughters as well as several other characters in the game, had tragically passed away before the game's release. Maus, 39, had passed away on January 24th, 2021, after a battle with colon cancer.