The game (especially the 'Umbrella's End' level) incorporates several elements from the first Resident Evil (2002) movie, such as: the Red Queen computer, an attack on a high-speed train wagon inside the Umbrella complex, the protagonists getting trapped in a room with lasers.

Unlike any other Resident Evil so far, most of the files you collect are profiles of each character and enemy ever appeared in the Resident Evil series leading up to the end of Umbrella.

This is the first Resident Evil game released to the Nintendo Wii console.

After the credits, Wesker sits down in the map/satellite room, but if you look carefully on the right side of the map room, you can see the map layout of the castle from Resident Evil 4 (2005), which will occur a year later.

Comic book style animation was used in the introduction and closings of each scenario.

In the final scenario (Fall of Umbrella), every non-boss enemy that ever appeared in all the previous Resident Evils is used in the final confrontation against Umbrella: Zombies, Crimson Heads, Lickers, Hunters, Spiders, Eliminators, Leeches, Bees, Bats, Neptune, Ivy Plants

Even though Leon didn't make an actual appearance, he is referenced a few times and pictured on one of the comic book style animations.

Considering that this game is a remake of several Resident Evil games, in the original Resident Evil 3 Nemesis game, you fight the grave digger worm underground, but in this game, you fight him on the street. Same thing with the Nemesis; you fight him on the roof of the police department, but in the original, he is fought multiple times up to the abandoned Umbrella factory in many mutated stages.

Considering that this game contains a remake of Resident Evil 3, the original Resident Evil 3 Nemesis game contained both Beta and Gamma species of Hunters, but in this remake game, there's only the standard Hunters that also appeared in Resident Evil 1.

The Raccoon City scenario shows no direct remake of Resident Evil 3: Nemesis (1999), because the city layout is of Resident Evil Outbreak (2003).

This is the first Resident Evil where Albert Wesker is a playable character in the main storyline.

This is the only Resident Evil game where a boss uses laser weapons for attack.

This is the first Resident Evil game where you have the ability to destroy objects: lamps, shelves, doors, pictures, lights, statues, anything in the rooms that's breakable.

This is the first Resident Evil where you have no control over the character's directional movements, you have to go where ever the game wants you to go.

This is the only Resident Evil game so far to grade you on just about everything: clear time, critical hits, files, objects destroyed, while the other Resident Evils (excluding Resident Evil 1) only grade you on your overall progress of the whole game. And this is also the only Resident Evil game where you can't possibly get a D or an E ranking, because the grading system only includes S, A, B, C ranks.

The scenario 'Fourth Survivor' has the second appearance of Agent HUNK's face in the entire series. It can be seen reflected in the vial containing the G-virus, although briefly and with some difficulty. In Resident Evil 2 (1998)'s '4th Survivor' mission, he could be seen without his mask at the end, but his face was only seen from the side. HUNK's full face could be seen in the epilogues of Resident Evil 3: Nemesis (1999).

One of the reasons for the high level of polish in this game is that time was saved on 90% of the areas and character models. By re-using design and graphical content from other games, and just adding a graphical face-lift, designers were able to spend more time polishing and less time building. Resident Evil 0 and Resident Evil (2002) were obvious choices for the Training Facility and Mansion scenarios. It is interesting to note that Resident Evil: Outbreak provides both scenery and models (zombies) to cover the Resident Evil 3: Nemesis portion of the story, as well as Ada Wong's side feature, and many textures of the final installation.

Mistakes

In-game files as well as Resident Evil related material state that the Tyrant T-103 was created after Umbrella recovered the research data from the original fight against the Tyrant in Resident Evil. Among the Tyrant T-103 specimens is IVAN, Sergei's bodyguard. The problem is that IVAN appears and fights Wesker in-between the events of Resident Evil 0 and Resident Evil which was about one day earlier than Jill or Chris fought the original Tyrant meaning IVAN would not be created for about two months as the necessary data to do so had not yet been collected.

On the train, the conductor's cabin is misspelled 'Conducter'.

The Player is the only one ever shooting in spite of there usually being two characters.

A map of the castle from Resident Evil 4 is displayed on monitors after the final credits. Those events don't happen for another year, and no Resident Evil character would know anything about the Resident Evil 4 region at this point in the time-line anyway.