This game covers the events of Resident Evil 2 (1998), Resident Evil - Code: Veronica (2000), and a new event in South America that was mentioned in a BSAA file.

This is the only Resident Evil game where Claire Redfield and Ada Wong meet.  In the original Resident Evil 2 game, Claire's supporting character is Sherry Birkin and Ada is Leon's supporting character.

The 'Game of oblivion' segment of this game is more closely based on the original Dreamcast version of Resident Evil - Code: Veronica (2000), rather than the extended and wider released version, Resident Evil - Code: Veronica X, which became available in 2001. Like in the 2000 game, Albert Wesker only makes a very brief appearance at the end of the Game of Oblivion segment, whereas in Code: Veronica X, he had several physical confrontations with other characters. A major difference with either version of Code: Veronica is that Alfred challenges Claire and Steve to a game, by sending them through a kill house in the basement of his Military Training Center. The kill house appears in no version of the original game.

Chronologically, this marks the first appearance of Jake Krauser, an evil traitor who appeared in Resident Evil 4 (2005).

In Resident Evil: The Umbrella Chronicles (2007), your score is ranked with stars (the better your score, the more stars), but in the Darkside Chronicles, your score is counted with numbers and gold that is collected throughout each scenario.

There's a new enemy in the South America scenario called the Jabberwock, named after the Jabberwocky in the story of 'Alice In Wonderland'. This may be a nod to the yellow Bandersnatch creatures in the 'Game of oblivion' section Resident Evil - Code: Veronica (2000), which were also named after a creature mentioned in Alice in Wonderland.

This game marks the most in-game files and archives than any previous Resident Evil game release at 237 archive files. This out beats the Umbrella Chronicles record of the most in-game files.

One of the bosses in the 'Operation Javier' scenario, Manuela's mother, is named 'Hilda'. This was originally meant to be the name of the character Alexia Ashford in Resident Evil - Code: Veronica (2000) (which is retold in the 'Game of Oblivion' scenario).

Unlike in Umbrella Chronicles, the camera's movements and speed gives to less aiming accuracy.

In Umbrella Chronicles, solid objects can be destroyed (for points), but in Darkside Chronicles, there are far less objects to destroy.

This is the only Resident Evil game where players can send their gaming scores (headshots, points, difficulty, ranking) to a network database, and players can view their score ranks as well as other players.

In Resident Evil 2 (1998), you meet Ben Bertolucci, but in the 'Memories of a Lost City' scenario in Darkside Chronicles, Ben is already slaughtered to death by William Birkin by the time you meet up with him. This scenario also omits the S.T.A.R.S. office, the subterranean factory, and the battle with William Burkin on the large elevator. Also, Birkin dies on the train when the lab explodes, not because the train self-destructs.

This game explains why Krauser became evil with a mutating arm in Resident Evil 4 (2005): he gets impaled in the arm by something that the infected Hilda shot at him, and he sees Leon as a cruel coward living in fear. He also had evil intentions all along, and faked his death in a later accident so he could seek out Wesker to help him battle the infection. Krauser later became Wesker's henchman, and set off the events that led to Resident Evil 4.

Unlike in Resident Evil - Code: Veronica (2000), this time you have to fight the monster Steve, instead of running from him.

Mistakes

In the level "Game of Oblivion" scenario 2, Steve screams "who are you callin' a rat?!" His mouth never moved.

Some Wii copies of the game is missing the Wii logo on the spine of the game's box cover.

During gameplay, the characters mouths don't match the words that they say.