The developers stated that this is both a 30th anniversary game and the final main story of the original saga.

The license plate of Leon's car, 9642, is a reference to all the mainline of games in the Resident Evil franchise where Leon Kennedy makes his playable appearances. Resident Evil 2, Resident Evil 4, Resident Evil 6, and Resident Evil Requiem as the 9th in the mainline.

Leon can find a locker containing Capcom swag from the Sega Saturn era, like a poster for Street Fighter Alpha (1995) and copies of Street Fighter Alpha 2 (1996), the original Resident Evil (1996), and Mega Man 8 (1997). There are also old tickets to the Raccoon Zoo inside -- a likely nod to the "Wild Things" scenario from Resident Evil Outbreak: File 2 (2004).

Grace was actually supposed to be completely safe in that gated area of the clinic. Gideon had to make sure she wasn't harmed as he needed her. The Girl was an unexpected complication that Gideon had set for termination before it broke out of the basement and got upstairs.

Zombies are confirmed to return as enemies. Though the developers state they will not make them predictable with the classic shambling walk.

From the trailers, at least one possible zombie was seeing flailing rapidly. Implying they have potential to be as formidable as the C-Virus zombies; which could use weapons, leap, and run when they saw the uninfected.

When exploring the Rhodes Hill Care Center, you will spot a strange label behind the bar lounge. Among the liquor bottles sits one that's labeled “Avernico”. When you unscrambled the letters, it actually spells "Veronica", which a reference to Resident Evil: Code Veronica.

Leon was initially considered as the sole protagonist, but this was changed to make him a B Scenario much like Resident Evil 2. Grace was advertised at first to return survival horror elements.

When Leon is driving into Racoon City he passes the gas station from Resident Evil 2 Remake. His jeep is still there, burnt out like the rest of the station.

It shows how far the missile explosion reaches. Meaning that the semi driver likely died after passing Leon, Claire and Sherry.

The sequence of letters you see after analyzing the Girl's hand in the laser microscope, GGC AAG AUA ACG UGU CAU, is actually a sequence of RNA codons for amino acids - Glycine, Lysine, Isoleucine, Threonine, Cysteine, Histidine - which spell out "GLITCH".

This is the first Resident Evil game since Resident Evil 4 (2005) to release day one on a Nintendo console, with Resident Evil 4 being released on Nintendo GameCube and Resident Evil Requiem being released on the Nintendo Switch 2.

Sherry Birkin is Leon's contact instead of Hunnigan because she took time off from the field.

The early concept artwork for Resident Evil: Requiem shows how there was originally going to be an alternate opening which would include different introduction for both Leon and Sherry. It shows two of them walking together and talking in some building, with Leon wearing different clothes. Possibly similar to how Grace is introduced in the opening of the final game, at her normal job.

Interestingly, an early version of the screenplay for the first Resident Evil film, which was left unused, changed the Cerberus monsters in a very similar way like how they were changed in Resident Evil: Requiem. In the first draft of Alan B. McElroy's screenplay from 1997, they are described as "mutated dogs the size of cars and with honey-comb like skin pattern which can heal any injuries they get." The concept art for Requiem shows how they were originally going to be just as big in the game.

It's confirmed that the missile that hit Raccoon City was only thermal and not nuclear. Which is why it's safe to go back to the ruins of the city 30 years later.

There's a good reason Racoon City is empty of any zombies outside of the buildings. The giant spiders and mutant dogs all likely ate them.

The Connections Commander is implied to be HUNK.

Mistakes

After Grace injects Leon with the cure, she removes his glove, few seconds later his glove reappears on his hand.

The video feed from a helmet camera shows the user being shot in the head, yet there is no bullet hole in the helmet when Leon searches him.

There is no hole in Grace's shirt where Victor Gideon's tentacle stabbed her.

There is a photograph with three men in it. On the back of the photograph it says 'Artificial Organ Transplant Experimentation Team'. An artificial organ is 'implanted', not 'transplanted'; 'transplantation' is where an organ is removed from another body.

When Grace uses the broken bottle her blood was being drained into to cut her bonds, blood somehow isn't still pouring into the opening despite the IV still being in her arm.

The platform that Leon and Grace escape Albert Wesker on has no motors or any visible means of propulsion; it simply moves on its own.

Victor Gideon's motorbike explodes after the fuel catches fire. Gasoline is flammable, not explosive.

The text on the notes does not match the text in the dialog that appears on the screen describing the text of the notes.

In Racoon City, there are papers on the ground. Given that over a quarter of a century has passed, any paper should have long disintegrated, and any photograph should have faded.

In the ruins of Raccoon City, a tower crane can be seen with a suspended load. A tower crane cannot possibly hold a load in suspension for 28 years; it would suffer a catastrophic failure after but a few months.

The panel that needs the square socket wrench to be opened is opened when the socket wrench turns to the right. Left is always used as the direction to unscrew.

There are explosive containers with detonators attached in the ruins of Raccoon City. The detonators shouldn't be working, as no battery can hold a charge for over 27 years.

In the ruins of Raccoon City, various signs of power can be seen, such as lights, and old generators can be started. 28 years have passed since Raccoon City was destroyed; nothing should be working at all.

In the ruins of Raccoon City, there are Infected left. Raccoon City was destroyed by a missed strike in an effort to contain the T-virus; even if any Infected survived the attack, they would have died or escaped by now.

A pair of side-cutters are used to cut through a bundle of steel wires. Side-cutters are meant to cut through softer metals and do not have the leverage needed to cut through a bundle of steel wires.

The description for a crank says that the crank is extremely rusty, yet it has barely any rust at all.

In certain places in Racoon City, the tackle of cable hoists must be shot to drop the loads that they carry. No cable hoist ever manufactured could hold in suspension a heavy load for 28 years.

The area with the bodies that move along a track in the ceiling activates by itself. Grace never flips any switch except for the robot arm with the lifting forks, and nothing else turns a switch.

The detonator for the C4 used to blow up a gate is unnecessarily complex; all that is needed to detonate C4 is a blasting cap.

Leon encounters zombies with chainsaws in the ruins of Raccoon City. Chainsaws are powered by gasoline, and gasoline becomes useless after a few years. Leon also must collect gasoline from a storage tank.

In the ruins of Raccoon City, Leon must move a very large object using a hand wheel. No object that large can be moved with only a hand wheel, even if the mechanism could have survived 28 years.

Leon finds and picks up a mechanic's jack in the Racoon City police station. It is highly unlikely that such a jack would work after 28 years.

When the main antagonist has Leon confined to a chair, he cuts Leon's neck with a scalpel. This appears to be near the blood vessels of the neck, the transection of which is fatal within minutes, yet Leon survives with only moderate bleeding.

A rocket fired from an RPG-7 is shown blowing the wreck of a car into the air. No man-portable rocket is explosive enough to do this.

Wesker uses a handgun to blow soldiers' limbs off. No handgun is powerful enough to do this.

Grace must 'activate' a zombie by putting artificial organs in him. The zombie dies and falls upon the floor, and leaves behind an I.D. bracelet. If the I.D. bracelet was with the zombie in question all along, Grace shouldn't have needed to 'activate' him at all; she should have been able to just find the I.D. bracelet on him.

Throughout the ruins of Raccoon City, papers are taped up. No adhesive of any kind that is office-grade can remain sticky for 28 years; such adhesives don't even last a quarter of that time-span.

Wesker ambushes several soldiers with a handgun. Given that he is using a handgun, he couldn't have gotten within firing range without being in range of their weapons, which he isn't.

After an Infected's hand is parted from her wrist by a falling elevator, the hand spurts blood. Unless a blood vessel is attached to a functioning circulatory system complete with a heart, blood cannot spurt like that.

When Grace is using the multimedia player, she doesn't select the file called 'Grace' before pressing Play.