Though young, Jake Muller is a seasoned mercenary, grinding out a living fighting for the rebels in Edonia. Life in the eastern European state suddenly changes with the arrival of a strange medicine, billed as nutritional supplements. Surprisingly, all who take the supplements begin to change; losing all human rationale, they transform into monsters. Jake alone is left unaffected.
Already confused by the chaos erupting at the base, the sudden appearance of U.S. agent Sherry Birkin only further confounds the young mercenary. Sherry explains that the so-called "supplement" is, in fact, the C-Virus: a horrible new mutation-inducing virus developed by the terrorist group Neo Umbrella. Jake however, as Sherry explains, apparently carries antibodies; this fact quite possibly makes him the last and only hope for humanity in fighting the virus, and is the reason Sherry needs his assistance. True to his mercenary nature, however, Jake insists that if he really is the key to saving the world, his help will come at a cost; an agreement of fifty million dollars for his services is met, and the two go to make their escape from the embattled camp.
At that same moment, Neo Umbrella unleashes a monstrous hunter, known as Ustanak, to pursue the two. Amidst the ensuing deadly game of cat-and-mouse, the pair run into Chris Redfield of the BSAA—Chris being the older brother of Claire, to whom Sherry owes her life. With Chris' help, the two manage to escape the scene via a BSAA helicopter. However, Ustanak's relentless pursuit continues. In the creature's attempt to capture Jake, the helicopter sustains massive damage and begins to crash. Sherry and Jake manage to bail out, however, as they near the ground, a piece of the helicopter tears through their parachute, causing them to fall.
Chapter 1-1: The Sewer
- Continue to the stairs to go above the Sewer. Open the door with your partner. While outside, a helicopter will appear and will start to shoot. You can avoid the bullets by staying on your left.
- Follow the open path, there will be several J'avo, but no need to kill them. Keep following the open path. The helicopter will start shooting missiles at the J'avo, so move on quickly to not get damaged. Continue to follow the open path. Open the door with your partner.
- After the cutscene, open the two boxes and grab the items, immediately after there will be a Green Herb laying around, if you're not careful your character will end up falling and you will have to complete a QTE to get up. Continue to the path leading to some groups of J'avo. You can either kill them all stealthily or shoot at them, it's better to kill them without being noticed so you don't waste ammo for future stages. Jump across a gap if you're Jake or go downstairs if you're Sherry. For Jake, help Sherry up, Immediately jump to a cracked floor and go upstairs, deploy a stair behind you so Sherry can follow you.
- Continue to a door and open it with your partner. Sherry and Jake will stare at the bridge where the BSAA is fighting some J'avo, immediately after you'll have to kill four of them, one is upstairs so use your gun.
- As Jake: Help Sherry up and use the swing bar Sherry drops to jump across the gap, a helicopter will show up and you must run to your left and complete one QTE to proceed. Another swing bar will be at the end and there will be a door immediately after, press the partner button and wait for Sherry to show up.
- As Sherry, Jake will boost you up and the camera will highlight a swing bar, go near it and press a button to drop it. Follow the path and two J'avo will be there, kill them and open a box and grab whatever it drops, there's a spawn point here to a few J'avo will show up, you can kill them as soon as they drop down with a charged Stun Rod attack. After you're done, follow the path and go left, open the door with Jake.
- After opening the door, J'avo will start spawning and shooting at you, ignore them all and run towards the door at the end of the road, open it with your partner.
Chapter 1-2: Water Channel
- After a cutscene, Ustanak will chase Jake and Sherry, they must run away. After you jump from a ledge, Jake must help Sherry to proceed after that they will break into a window in a building.
- Go through the men's restroom, kill the only J'avo there and get the Green Herb laying around, Jake can boost Sherry up so she can grab skill points and a Red Herb. Then open the door on the right that will lead underground, a J'avo is there, kill it and open the boxes to grab ammo and Skill Points, come back and open the door leading to the next stage.
- Proceed to the left, go downstairs, continue to a door then open it with your partner. As soon as you break in, 3 J'avo willdrop in by rope. Shoot the oil drum to their left to kill them immediately. Go up the stairs and grab the Magnum, then to door downstaris, open it with your partner. Ustanak will drop in then dashing to the door to prevent you from escaping.
- Player now must defeat Ustanak. Some oil drums are scattered all over the stage, shoot them when Ustanak is near them to make more damage.
- As soon as Ustanak isdefeated a (cutscene) will trigger, players will fall below, leading to new path.
Chapter 1-3: Underground Passage
- Proceed through the path, obtain some items, then keep going, leading to a piles of Mannequin. Keep moving until they're outside.
- There is a Serpent Emblem visible when you exit from the Ruins. Use the Handgun to shoot it. Continue left, there will be 2 J'avo guarding the gate, kill them then open the door with your partner.
Chapter 1-4: In Front of City Hall
- A big B.O.W. appeared after cutscene, but it's useless to use weapons to kill it. Now player's objective is Help the BSAA, by taking down Anti-Aircraft guns. Follow Chris' team.
- To defeat the giant B.O.W, you must stun it by shooting its face or weak spot (the red-ish muscle on his back). Then, make sure you are on 2nd floor to attack near it using the attack button. This method needs to be repeated if the difficulty is set to Normal or higher.
- When 2 Anti-Aircraft guns destroyed, follow Chris' Team below into Underground Passage to get to the last Anti-Aircraft gun. There are some items in the Underground Passage. The 2nd Ogroman will appear, which is the one that was "lost" in Chris' Campaign.
- If you didn't kill the 2nd B.O.W and helped the BSAA destroy all Anti-Aircraft guns, you will need to stun the B.O.W then attempt to pull something out of its back to expose his weak spot.
- A Missile sweep from an Aircraft attacks the exposed organ from the B.O.W. As soon as the B.O.W is defeated, a cutscene will start.
Chapter 1-5: Inside the Helicopter
- Ustanak will attempt to crash down the Helicopter. Player must shoot at Ustanak to progress the battle, there is Handgun ammo and a First Aid Spray inside the Helicopter. Ustanak can be located by a red marker in the HUD.
- As soon as the Helicopter cannot fly much further, the pilot asks them to move to another helicopter by jumping through the door.
- When players are in the 2nd Helicopter, Ustanak returns with some other Helicopter. There are Gun Turrets, use them to destroy the Helicopter where Ustanak is. Shooting at Ustanak is useless. Their Helicopters will shoot missiles towards the players, they must shoot at them.
- After Ustanak's Helicopter is destroyed, he will attempt to kill Jake and Sherry by grabbing onto their Helicopter to make them slide down. The player must shoot the Gas Tank (looks like a Fire Extinguisher) and complete a QTE. Then a cutscene will start.