Resident Evil: The Darkside Chronicles is a follow-up to the million-selling Resident Evil: The Umbrella Chronicles. The game touches upon the main Resident Evil titles not represented in The Umbrella Chronicles, namely Resident Evil 2, Resident Evil Code: Veronica, and an entirely new story which serves as a prequel to Resident Evil 4. Like its predecessor, the game was a Wii exclusive that is now available for download on the Playstation Network.
A drug lord Javier Hidalgo has disappeared after attempting to contact Umbrella. Leon S. Kennedy and Jack Krauser have been sent to South America to find him. They approach a coastal village with the intention of meeting a contact who will guide. Krauser is a bit skeptical about the existence of Bio-Organic Weapons (B.O.W.s), but knows that Leon has encountered them in the past. As they enter the village, a radio news report talks about the recent disappearance of more than fifty teenage girls. Soon afterwards, Krauser gets first hand confirmation of their existence, as zombies and other monsters attack.
They find the guide alive fatally wounded. He tells them that he helped a girl escape from Javier's mansion, but she brought devils with her. The Leon and Krauser make their way to the church where they find the girl, who appears to be wounded with a bandage around her arm. She's singing as a monster listens on. The girl passes out, and the monster notices the the two intruders and attacks. The two are able to chase the monster away, and Krauser decides that it's time that Leon tells him everything he knows.
Leon then retells the story of his first day as a police officer of the Raccoon City Police Department, when Raccoon City was overwhelmed by the T-Virus. He met Claire Redfield and together they learn the city has been infested by zombies. They make their way to the police station for safety, only to find the police station has also fallen. There is a survivor, a little girl named Sherry, but she is frighted at their appearance, and runs. As they attempt to save the girl and escape alive, they discover she is the daughter of two scientists, Annette and William Birkin.
In the sewers beneath the city, the run into Annette, and she tells them that the creature chasing Sherry is her husband, William. After being shot, injected himself with a new virus he and Annette had been working on, the G-virus. William manages to catch up to Sherry, and In his transformed state, his drive to procreate leads him to infecting his daughter with the virus. Leon and Claire manage to reach the cure in an underground Umbrella facility and cure Sherry, then kill William Birkin and escape from the city alive. Claire sets off to continue her search for her brother, while Leon is pressured into working for the US government.
The story returns to South America. The girl wakes up and says her name is Manuela. She agrees to lead them to Javier. They make their way up a river to a dam controlled by the drug lord. The dam is also infested with zombies, and other monsters, like the village was. They have to fight their way through because Javier's mansion is on the other side.
Within the dam, Manuela is attacked by a zombie and runs off scared. When Leon and Krauser catch up with her, they find her singing again. She explains that when she used to be scared, her mother used to sing her that song.
Javier tells Manuela to come home to him over the speaker system. Manuela runs to the next room yelling out "Father!". Javier, himself, is standing in the next room, and tells her that she has to be patient. She only needs to accept his directions for fifteen years to prevent the transformation, and that the man who gave him the Veronica virus said it would work. Some of Javier's men grab Manuela from behind as a flood of water comes flooding into the room. Manuela breaks free and jumps after Leon and Krauser as they get swept away.
As they wash away, Leon's thoughts revert back to what he knows of the events told to him by Claire about the Veronica virus. Claire had been searching for her brother, Chris Redfield, in the Umbrella Paris facility when she got caputured and taken to an Umbrella training and prison facility on Rockford Island. She meets another prisoner, Steve Burnside, and together they try to find a way off the island.
They run into the commander of the island, Alfred Ashford, who couldn't get past the absence of his sister, Alexia. He began dressing as his sister and having conversations with himself. Claire and Steve secure a key to a plane from Alfred, however, once they are in the air, the discover that they are not in control and Alfred directs the plane to an Umbrella facility in Antarctica.
Alfred attempts to kill Claire and Steve again, and once again he fails. However as Claire and Steve make their escape, Alfred awakens his sister, who had been in hibernation for fifteen years after injecting herself with the Veronica virus. Alexia attacks and the two are captured.
Meanwhile, Leon had used his government resources to track down both Chris and Claire Redfield. He contacts Chris and tells him about the danger his sister is in. He made his way to Antarctica and finds Claire. Alexia tells them that her experiment awaits them in the coliseum.
When they reach the colisuem, they find Steve after having been injected with the Veronica virus. Without the hibernation process that Alexia went through, his mutates before their eyes and attacks them. Claire and Chris nearly succeed in defeating him, then Alexia moves in to kill them. Steve gains control of himself and frees Claire, and then Alexia finishes him off.
Chris and Claire then have a final confrontation with Alexia. After they defeat her, they return to the coliseum to find Steve's body gone. A message carved into the wall let's them know that Chris' ex-team leader, Albert Wesker, is responsible, and now has a sample of the Veronica virus in his hands.
The story returns to South America once again. Leon and Krauser reunite with Manuela. Leon eventually questions her about what's going on and she unwraps the bandage around her arm revealing a diseased arm underneath. Her mother had the same fatal disease, that only affects people in the area, and her mother did not survive. She says she was injected by the Veronica virus as a as part of her treatment.
Before they get to Javier's mansion, Krauser suggests they should just take care of the girl before she becomes a problem. Leon counters that he has to learn how Javier is keeping the virus at bay, and shows Krauser that he has special orders from the president to eradicate the virus once and for all. Krauser agrees, while internally he realizes he is more of a pawn than a player.
Inside the mansion, they find a room of human organs, and refrigerator of human bodies. All the reported missing girls. Javier appears and tells them that Manuela's organs had to be regularly transplanted to keep away her pain and keep the virus at bay. Javier then commands the monster from the church to attack., which Krauser welcomes because he wants to prove how valuable he can be to his government.
While fighting the monster, Maneula's singing distracts the monster. As they defeat it, Krauser is badly wounded with one of its spines. He says he's fine, while thinking that it is now the end of his military career. As the monster dies, Manuela realizes it was actually her mother.
The scene shifts to Javier, and he allows himself to be swallowed by a giant plant in his greenhouse. He merges with the plant and attacks Leon and Krauser. They try to escape with Manuela, but eventually decide they have to make a stand.
While confronting Javier, Manuela decides to accept her pain as a sign that she's still human, and decides it would be better to die rather than transform into a monster and so she runs towards her father. Leon rushes in to stop her, and tackles her to the ground. Javier raises one of his limbs to crush them, and this time Manuela is the one that pushes Leon out of the way. She raises her diseased arm and it bursts into flame, stopping Javier. They get to their feet, and Manuela continues to fling some of her combustible blood at her father as Leon and Krauser finish him off.
They three of them fly off in a helicopter. Manuela says she should have died with her father. Leon counters that no one should have died, and that she has an obligation to live for the sake of the girls inside of her. Manuela is taken into custody by the US government.
Meanwhile, Krauser is forced to leave the army. He is amazed at the power that Manuela had, and wonders who exactly Wesker is, and if he would be able to help him regain his strength.
Notable differences from Umbrella Chronicles is the addition of a more intense and "shaky" camera too add tension to the presentation. Similar to its predecessor, ammo, health (green herbs and first-aid spray), and gold can be found during gameplay and carried over from each level. Gold found during the level or at the grading screen at the end of each mission can be used to upgrade weapon grades. Upgrades include reload speed, stopping power, and the strength of each weapon. There is no restriction to when you can switch weapons from storage and assign them to the direction pad.
Unlike in The Umbrella Chronicles, the player's partner character will occasionally be visible on screen in the single-player mode, both to assist in shooting and to be rescued. The second character will always be present, whether or not there is a second player controlling him. Occasionally, the game will present alternate routes through a level.