Raid on the Spencer Estate: In 2006, the Bioterrorism Security Assessment Alliance receives intel on the whereabouts of Umbrella's founder, Oswell E. Spencer. Jill Valentine and Chris Redfield are ordered by the BSAA's European Headquarters to apprehend him, they accept the mission in hope of uncovering some info that might lead them to Albert Wesker.
The game starts in 2009, six years after the destruction of Umbrella and 11 years after the destruction of Raccoon City. Chris Redfield is sent to investigate possible Bio Organic Weapon smuggling in Africa. Upon arriving in the Kijuju Autonomous Zone, Chris meets his partner, Sheva Alomar of the BSAA West African branch. Together, they attempt to rendezvous with the BSAA's "Alpha Team", who were attempting to intercept a B.O.W smuggler named Ricardo Irving. By the time Chris arrives in the city, most of the townspeople have already been infected with Type 2 Plagas, although they initially refrain from attacking Chris and Sheva (since they have not yet been ordered to), instead either ignoring them or giving them hostile glares. However, the situation quickly escalates as their local contact is publicly executed and the crowd's agitator discovers their presence, resulting in an open confrontation between the two agents and crowds of Plaga infected Majini.
Barely escaping from the Majini, Chris and Sheva make their way across town and find Captain DeChant, the only remaining member of Alpha Team. DeChant is fatally wounded, however, and warns them of Irving's deception before handing them a data file and succumbing to his injuries. Soon afterwards, the two find themselves face-to-face with a bizarre and dangerous creature, seemingly made of leech-like worms, with Chris correctly assuming that it was responsible for the destruction of Alpha Team. They destroy the creature by locking it in an incinerator room and activating the flame throwers, and then send the newly acquired data to headquarters. Later, the West African BSAA Delta Team finds and rescues the pair from a crowd of Majini on motorcycles, and Captain Josh Stone, leader of Delta team, gives Chris a memory card containing images of research material. Among these is an image of Chris's supposedly dead partner and close friend Jill Valentine. Chris and Sheva continue their search for Irving and eventually corner him in a building beyond the mines, although he escapes with the help of a mysterious hooded figure (later revealed to be a brainwashed Jill) and unleashes a bat-based B.O.W on them. After they defeat the monster, BSAA agent Dave Johnson shows up in a Gambit and escorts them across the savannah (as they are pursued by more Majini on motorcycles) to rendezvous with Delta Team, unaware that they (with the exception of Josh Stone) have already been wiped out by yet another B.O.W. They arrive to find all of their comrades dead, and Dave himself is crushed underfoot shortly afterwards (as an homage to the first appearance of El Gigante, a B.O.W from Resident Evil 4 on which this new B.O.W is based). Chris and Sheva use the machine guns on the back of an Gambit to battle the monster, eventually defeating it. Once they do, they are ordered to leave the area and report back to headquarters, to which Sheva initially agrees. However, Chris is determined to find Jill and elects to continue his mission anyway, prompting Sheva to change her mind and follow him. Using the data the procured from the mines revealing the real location of Irving's scheduled transaction, they head for an oilfield beyond the marshlands.
It is during this time that Chris reveals the truth behind Jill's supposed "death". In 2006, three years prior to the game's events, Chris and Jill were working to track down Albert Wesker. They attempted to gain answers from Umbrella's former President, Oswell E. Spencer, after they learned of his location, hoping to apprehend him as well. However, they arrived at the estate only to find Spencer dead at the feet of Wesker himself, initiating a battle. The pair were no match for Wesker, who eagerly prepared to finish off his hated rival Chris once and for all. Jill, sacrificing herself for Chris, tackled Wesker through a nearby window looming over the surrounding cliffs. Unable to find either of their bodies, the BSAA was forced to assume that both had died in the fall.
Arriving in the marshlands, they travel through a small village inhabited by the Sodibaya, an indigenous tribe who were infected with Type 3 Plagas by Irving after he told them that it was a vaccine against a deadly disease (which, in reality, did not exist). As they escape the village, they discover a pair tents belonging to TRICELL, along with a series of notes implicating the company in the spread of Las Plagas throughout the region. Chris and Sheva reach the oilfield soon afterwards where they once again encounter Josh Stone (injured, but alive) and Irving, who responds to their presence by blowing up the entire facility and escaping on his boat. The BSAA catch up with Irving's boat, however, and corner him. With no other options left, Irving injects himself with a Dominant Species Plaga sample provided to him by Jill, and uses it to try and defeat the BSAA agents. Using the machine guns mounted on Irving's ship, Chris and Sheva destroy him despite his "extreme makeover". He blames his predicament on Excella Gionne, director of TRICELL's West African division, further implicating them of involvement, before telling the two agents to search in a nearby cave where they can expect to find all of the answers they're looking for.
Chris and Sheva head for the caves and discover an underground civilization that is home to more Plaga infected Sodibaya, who are guarding a long abandoned grotto containing a mysterious flower known as 'Stairway of the Sun', which the agents would later discover is the source of the Progenitor virus. Journeying deeper into the area, they ind a research facility that was once used by Umbrella but has long since been taken over by TRICELL. When they come upon the pods seen in the research material they acquired earlier, Chris frantically searches a nearby computer for Jill's location. However, an enormous B.O.W named U-8 appears before they are able to do so. Defeating the monster, they proceed to find Jill's name in the computer only to discover that the pod which held her is now empty. Excella Gionne appears on screen and tells them to leave, denying any knowledge of Jill, and ultimately revealing that she was the one who ordered the BSAA to evacuate after they defeated Ndesu. Deeper into the lab, Chris and Sheva encounter Excella once again, but she unleashes another creature similar to the one that wiped out Alpha Team, which they are forced to destroy with a flamethrower. They later encounter Jill in an underground cavern, and Chris fires a stray round which knocks away her mask, prompting Wesker to finally make his appearance. The agitated Chris is quickly left speechless when Wesker reveals that the mysterious hooded woman is Jill. Chris attempts to reason with her, but she attacks him with a flurry of hand to hand moves and starts an intense battle. Wesker arrogantly claims that he can spare only seven minutes to fight them, and eventually leaves the task to Jill.
Chris again calls out to Jill, and she attempts to resist the P30 used to control her. Wesker then activates a device, causing her great pain and administering more P30. In the process, she rips off part of her jumpsuit revealing a device attached to her chest. Jill attacks Chris and Sheva again, and they work together to subdue Jill and remove the device from her chest that is administering the P30. Chris then cradles the severely weakened Jill and she apologizes to both, stating that she was fully aware of her actions but could do nothing to stop them. She tells Chris and Sheva that she will be fine, and orders them to stop Wesker. Chris objects, but grudgingly agrees when Jill questions "Don't you trust your partner?". As they leave through an elevator, Jill says: "You're our only hope to survive this".
Chris and Sheva manage to board Wesker's ship and soon locate Excella. She flees with a briefcase containing various chemicals, dropping a few syringes in her haste, which Sheva collects. They eventually catch up to Excella once more, although she is now infected with Uroboros. Wesker calls out over an intercom, casually discarding the heartbroken Excella; she believed that she would rule alongside Wesker in his envisioned utopia, but he only saw her as a pawn. In response to this, Chris comments "Wesker doesn't give a damn about anyone but himself". Simultaneously, the Uroboros leeches burst from Excella, killing her and consuming the surrounding pile of corpses. The resulting monstrosity is nearly big enough to sink the entire ship, forcing Chris and Sheva to use a Satellite Laser Device to destroy it. Afterwards, they continue to pursue Wesker, who reveals his plan to spread Uroboros around the globe with a bomber, destroying most of humanity and ruling over the survivors as a god. Jill then calls and informs them of Wesker's weakness: regular doses of a serum called PG67A/W. Overdoses would weaken him, and Sheva realizes that the case Excella dropped earlier contained the serum.
After doggedly pursuing Albert Wesker across the wilderness, Chris and Sheva find themselves in the bombers' hangar. Wesker had stocked the plane with enough Uroburos-carrying missiles to infect the entire planet. In the ensuing struggle, Chris manages to inject Wesker with an extra dose of the serums Excella dropped. This greatly weakens Wesker, causing him to flee and escape to his Jet, although Chris and Sheva are able to catch up to him. Wesker reveals that the bomber is now climbing to the ideal altitude for global saturation, and that he plans to unleash the virus shortly. Chris and Sheva continue to fight Wesker, with the former injecting him with yet another dose of the serum. He is then blasted out of an airlock by Chris, but manages to grab onto Sheva. Tortured by his memories of Jill in the Spencer estate, Chris jumps forward and catches Sheva's hand after she loses her grip, refusing to let her share Jill's fate. Sheva shoots Wesker in the face, and he falls into the caldera of an active volcano. The bomber itself crashes into the same volcano soon afterwards.
The two agents are shocked to find that Wesker is still alive. Having finally lost all that remained of his sanity, he plunges his right arm into an intact Uroboros missile, and is immediately engulfed by the virus. The Uroboros-empowered Wesker pursues Chris and Sheva throughout the volcano, ranting about his visions for the future of mankind. But as Chris gains the upper hand in the fight, Wesker's sanity deteriorates even further, refusing to accept defeat and screaming "I can't lose, not to you!!!". Eventually, the heaving volcano causes the ground to crack and melt, sending Wesker tumbling into the magma. Josh, piloting a BSAA helicopter, spots the pair, and Jill Valentine kicks a ladder down to them. Chris and Sheva barely escape as the ground melts beneath them.
Enraged and defiant, even in the face of his own mortality, Wesker attempts one last gambit, snagging the BSAA helicopter with his monstrously mutated arm. Jill tells Chris and Sheva to use the RPG-7s mounted on the rear. The two partners send a pair of anti-tank rockets racing down into the corrupted face of Albert Wesker, ending his life in a cloud of flame and ash.
As the chopper flies away in the final cutscene, Chris remarks: "More and more, I find myself wondering if it's all worth fighting for". He looks at Sheva and Jill and concludes with: "For a future without fear.....yeah, its worth it". The game ends with the chopper flying into the dawn.