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The game is separated into two sides: the U.S.S. side and the SPEC-OPS side (Playable in DLC). Each side has seven chapters, where players can choose four of the six playable characters per side.

U.S.S. storyline

U.S.S. Delta Team (Also known as "Wolfpack") enters the Raccoon City Underground Laboratory, where they meet up with U.S.S. Alpha Team leader HUNK. Their mission: to assist the Alphas in stopping Dr. William Birkin from handing over his G-Virus research to the U.S. Military and retrieve the G-Virus. On their way to Birkin's lab, they find that Birkin has paid-off numerous U.B.C.S. mercenaries into working for him while the deal goes forward. When they reach Birkin's lab, the doctor is shot at from behind a closed door, HUNK and another Alpha leave with the samples. Heading up the elevator to meet up with GOBLIN 6, they soon find that Birkin has survived the attack and injected himself with the virus. The creature proceeds to kill off most of Alpha team before disappearing; HUNK offers to go back in search of the sample.

Not long after the battle, it becomes evident that the T-Virus has leaked citywide, and people are beginning to turn into zombies soon after. In what they see as a punishment by U.S.S. Command, Delta team is ordered to remove evidence of Umbrella's role in the outbreak. Heading into Raccoon City Hall, Delta Team meets with a U.B.C.S. mercenary, Nicholai Ginovaef and montior him. However, he is soon revealed as a traitor and attempts to kill the Wolfpack.

Later, the team is sent out around Raccoon Park to find the Nemesis, which has gone rogue. A second parasite is injected into its body in order to bring it back under control. Shortly after this mission is completed, the team is then sent out to the Raccoon Police Station, ordered to kill any surviving police officers and destroy evidence linking the company to the outbreak. When this is all done, the team exits the station, and soon after encounter rookie R.P.D. Officer Leon S. Kennedy, whom they begin to hunt down.

The Wolfpack chase Leon through a dozen streets despite his pleas to stop shooting at him. U.S.S command grow anxious and abandon Wolfpack in favor of Plan B (The deployment of several T-103s and Hunters from drop pods). Eventually, after a lot of fighting, Leon successfully evades the squad and they decide to find shelter for a breather.

They mop up a small Spec Ops force at a barricade outside City Hall, as well as a pack of Hunters. The Wolfpack then find themselves ambushed by two T-103s and barely manage to take them down. The team retreats into an abandoned Barber shop to catch their breath, making failed attempts to get back in touch with U.S.S command.

Shortly after that, Wolfpack are making a last stand and take down just over 1000 B.O.W.s attacking their position, Umbrella command decides to give the team one final chance and order them to return to Birkin's lab to find Leon. The team find themselves back at square one and eliminate countless enemies as they make their way through the labs.

They engage in battle with Ada Wong briefly before she makes her escape. The self-destruct sequence activates and the Wolfpack see Leon kiss Ada and her supposed death on the control room's camera monitor. Wolfpack then fight their way to the power room to find Leon and Ada missing. With little choice left, they abandon the facility but not without fighting the Super Tyrant which emerged from the boiler earlier on.

Eventually, U.S.S. Command finds the location of Leon, who are also with Claire and Sherry, and sends Wolfpack over to Lonsdale Yard where they have teamed up with whatever is left of the Army Spec Ops to defend the train yard. The Wolfpack break through their lines despite Claire's attempts at decimating them with a grenade launcher as well as massive mobs of Crimson Heads and zombies.

With Claire going into retreat, Leon comes out of hiding with a sniper rifle firing at the Wolfpack. The Wolfpack then fire upon the spec ops guarding Leon's platform and cause a soldier to bleed heavily causing a blood frenzy amongst the B.O.W.s. They smash down the barricade and overwhelm the last of the Spec Ops.

Wolfpack make their way to the ladder and subdue Leon using him as bait to lure Sherry and Claire out of hiding. Leon questions what they fight for and the Wolfpack engage each other 2 on 2. The defenders of Leon believing they can use him as leverage for evac, whilst the assassins believe carrying out these orders will finally earn them evac as well.

Saving Leon Ending

The player character and one other member of Delta Team are forced to kill their former comrades, who argue that Leon S. Kennedy must die in order for the mission to be completed. Afterward, they capture a wounded Kennedy, along with Claire Redfield and Sherry Birkin. However, they disregard U.S.S. Command's instructions to immediately execute the R.P.D. officer, hoping to use their hostages as leverage for negotiation. Command is outraged by Wolfpack's defiance and refuses to make a deal with traitors, thus causing the former U.S.S. operatives to sever their allegiance to Umbrella.

With no further use of Kennedy and his companions, the remaining members of Wolfpack allow them to live, partly to spite Umbrella as well. As they move to depart from the ruins of Raccoon City, the two survivors vow to destroy the Umbrella Corporation from within.

Kill Leon Ending

In the alternate ending of the U.S.S. campaign, the player character and one other member of Delta Team remain faithful to the Umbrella Corporation, although two other operatives betray the company by protecting Leon. After executing the traitors and Leon, the surviving members of Wolfpack capture Claire Redfield and Sherry Birkin. Contacting U.S.S. Command to report the successful completion of their objective, Wolfpack is instructed to kill Claire and deliver Sherry to Umbrella. Claire pleads for mercy, but the player character simply states that they are following orders, shortly before shooting her in the head.

Spec Ops storyline

United States Spec Ops team Echo Six is deployed to Raccoon City to investigate an epidemic. Upon arrival, they quickly determine that the city's residents have become zombies. Investigating further, they come to the 777 RC-Radio station, where they are attacked by USS operatives. They take and defend the building until reinforcements arrive. Proceeding toward the Raccoon Police Station, they encounter a survivor, Jill Valentine, but they are ordered not to share their mission objectives with her. She advises them to go instead to City Hall to find answers, but the group is attacked by the Nemesis-T Type. Echo Six defends Jill and helps her to escape. Soon afterward, they defend a team of Spec Ops soldiers from USS agents and Nemesis, and ultimately manage to incapacitate the creature at a STAGLA station.

Echo Six proceeds toward City Hall, stopping to erect barricades in alleys to keep the street outside clear. They find a heavy USS presence within, and defuse three bombs set up to destroy City Hall and the evidence it contains. In the records room, they find evidence of an Umbrella laboratory built beneath the city.

En route to the laboratory, the team sees Nemesis shoot down a helicopter, which crashes into the Saint Michael Clock Tower. Investigating, they find UBCS soldier Carlos Oliveira and an unconscious Jill Valentine. Echo Six offers to distract Nemesis while Carlos gets Jill to safety. They take advantage of Nemesis and its rocket launcher to blast open a grate leading to the sewers, which they use to escape the creature. The sewers take them to a steel foundry, where they once again encounter Nemesis. They use the foundry's vast supply of molten steel to incapacitate the creature one last time.

Continuing through the sewers, the team encounters Claire Redfield, who is looking for Sherry Birkin. They travel together for a time, splitting up to look separately after encountering William Birkin in a mutated state. Eventually, they find Sherry and escort her until she is reunited with Claire. Echo Six encounters Birkin again outside the entrance to the B.O.W. Programming Laboratory, where they use burning gas jets to subdue him.

Echo Six enters the laboratory, which is defended by a heavy USS presence. Within, they find a T-103 Tyrant being programmed to search for Sherry, and they learn that she is carrying a sample of the G-Virus. They attempt to halt the programming process, and in so doing they awaken it. Echo Six escapes, setting off the laboratory's self-destruct system in the process. As they escape, the Tyrant is set upon by NE-β Type parasites and transforms into the Parasite Super Tyrant.

One of the last strongholds of the USS in the city is the Incineration Disposal Plant P-12A, also known as the Dead Factory. Echo Six proceeds through a cemetery toward the plant, destroying several turret guns placed to stop them. Once they are inside the plant's incinerator room, Four Eyes springs an ambush of six T-103 Tyrants. Echo Six requests reinforcements and receives a Paracelsus Rail Cannon that helps them make short work of the Tyrants.

By this time, Leon, Claire, and Sherry have reached an extraction point at Lonsdale Yard, but they are under assault from USS forces. Echo Six arrives to defend them, and they also kill the Parasite Super Tyrant. The final blow is a hand grenade jammed into a gaping wound in its belly. Leon, Claire, and Sherry are extracted by helicopter, but Echo Six is informed that they need to remain in Raccoon City to deal with a new threat that apparently only they can stop.

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