The game takes place over a period of at least six months from December 2012 to June 2013, over fifteen years after the US Government's destruction of Raccoon City, and takes place in various places around the world.
June 29, 2013
In the United States - President Adam Benford is about to "come clean" over the incident in Raccoon City in a seminar at Ivy University, Tall Oaks, when he himself mutated into a zombie during a surprise bioterror attack led by an unknown organization. A man at the university guides Leon S. Kennedy and his partner, Helena Harper, through the campus in the search for his missing daughter, Liz. During the search he starts coughing and begins to make suspicious complaints of T-Virus Infection. They eventually find his daughter, only for her to turn into a zombie and eat her father in an elevator before turning on Leon. After they break out the elevator, they fight through a parking lot and into a surveillance room. Following on from there, the partners fight their way through the University to a police car and attempt to drive off, only to be flipped, causing them to use the sewer tunnels nearby.
This led the pair through the train lines and into the center of Tall Oaks to find the entire city infected. Fighting through the streets, they make it to a gun store where they meet up with other survivors: a couple and a police officer. After Leon and Helena fight off the intense horde in the gun shop, they are allowed upstairs by the gun store owner, only to be assaulted by a greater number of zombies. Eventually a school bus meant to bring the survivors to safety arrives, and the survivors escape except for the gun store owner who is dragged out of the window of the bus and also the Japanese tourist who tries to save him but fails.
During the incident in the city, Leon is informed by Hannigan that the city has been overrun, and that about 70,000 people are expected to have become infected. An organization named "Neo-Umbrella" had claimed itself as responsible for the event.
Chapter 2 begins on the bus as they drive through heavy rain to reach the cathedral. The driver attempts to run over a zombie but this sends the bus teetering off a cliff. As all the survivors are killed gruesomely by a nearby horde, the bus falls off the cliff leaving Leon and Helena as the sole survivors.
Making their way through a cemetery and eventually the front door of the cathedral, they are stopped by a man inside the cathedral who starts ringing the church bells. After surviving the incoming attack they are let into the cathedral, but Helena finds that the passage way is not open yet.
After searching the cathedral and solving various puzzles, the passage opens but a Lepotitsa emerges. Infecting survivors with its gas, Leon and Helena kill the abomination and enter the underground facility. Helena finds what she was looking for, her sister Deborah Harper Leon also finds a video labelled "Happy Birthday Ada Wong ", which depicts a confusing birth of a woman who looks like Ada. Deeper in the facility, they find Deborah, who already experiencing intense pain. She turns out to be infected with the C-virus and turns into a Chrysalid, and later mutated into a nude woman with large appendages sprouting out her back. With the help from Ada Wong, the three are able to defeat the mutated Deborah.
Chapter 3 begins after Deborah is killed. Hannigan contacted Leon, only to be interrupted by Derek C. Simmons, who immediately declared Leon and Helena as the prime suspects of the bioterror attack, while at the same time denying any accusation of him being the true mastermind.
Leon and Helena escape through the catacombs and are attacked by a shark-like B.O.W. which hunts them from the flooded catacombs into an underground waterfall, where the two managed to blow it with explosive barrels. As they drop out from the waterfall, they witness the thermobaric sterilizing of Tall Oaks, just like Raccoon City. Hannigan informs Leon that Derek C. Simmons just left the Field Operation Support in a hurry and is headed for China. Leon asks Haningan to fake his and Helena's death as they follow Simmons to China.
June 30, 2013
Chapter 4 begins as Leon Kennedy and Helena Harper finds out the plane they ride to China had been infiltrated by a Lepotitsa. The monster was defeated by letting it to fall from the plane's cargo hatch, but not before it spew airborne C-Virus which immediately infects every passengers on the plane. Leon was forced to take over the plane's control under Hannigan's guide while Helena fends off the zombies. After an intense, brief flying tutorial, Leon managed to crash-landed the plane on a cargo bay.
Surviving the ordeal, the two meets up with Sherry Birkin, a DSO agent sent by Simmons, and Jake Muller, the son of Albert Wesker. The reunion was short however, as Jake's hunter, Ustanak, arrived to capture Jake. Together they succeeded in driving away the Ustanak by letting a burning communication tower to fall on it.
Separated, Leon and Helena continued their search for Simmons through an indoor market. The two are forced to journey through the market, battling their way against a horde of humanoid creatures capable of dismantling their body parts.
Later, the agents came across an Ada-lookalike woman and her pursuer, Chris Redfield and Piers Nivans. After a tense argument on whether they should kill her or take her to custody, the woman manages to escape them. Piers and Chris set off to track her down, while Leon and Helena continue to look for Simmons, which they found soon, along with Sherry and Jake. Expecting them to bring him down, Simmons ordered his men to kill the four, but soon a J'avo shots him with a C-Virus. Fleeing himself, Simmons jump on a train where Leon and Helena chased him. The C-Virus infecting him transforms his body onto a centaur-looking beast, hellbent on killing the two agents. However, the combined firepower of Leon and Helena's weapons brought him down.
Simmons falls to the ocean below as the Family decided to leave him to be destroyed by the BSAA, or anyone for that matter.
December 24, 2012
Jake Muller, a mercenary of the fictional South-Slavic Edonian Liberation Army flees from the authorities during a bio-terrorist attack. There he partners up with Division of Security Operations (DSO) agent and Raccoon City survivor Sherry Birkin, who needs Jake because of his rare antibodies that could lead to an antidote for the C-Virus. Jake agrees, but only if he receives $50 million in return. Soon, they find out that a robust creature is chasing them down. Evading the creature as best as they could, the two eventually meet up with the BSAA Alpha Team, led by captain Chris Redfield, who by all accounts sees something special in Jake's facial structure. The reunion was short due to the presence of the ambush of a J'avo army, bringing a pair of behemoth-like B.O.W.s.
Sherry and Jake's extraction from Edonia by the BSAA is sabotaged by a B.O.W. codenamed 'Ustanak', forcing the pair to crash into the mountains, there we find out that due to the G-Virus that is still dormant in Sherry's system, Sherry now has a regenerative healing ability. After making it to the other side of the mountains, both Jake and Sherry are captured by Neo Umbrella, where "Ada Wong" tells Jake his real father was bio-terrorist Albert Wesker. For the next six months both Jake and Sherry are subjected to numerous tests by the bio-terrorist group.
June 30, 2013
Jake and Sherry manage to break out of the Neo Umbrella facility, only to find themselves in Lanshiang, China. Sherry manages to get in contact with her superiors and sets up a rendezvous in China. On the way over to the rendezvous, they both witness a U.S. Government plane crash into the city, where they find the two survivors of the crash, DSO agent Leon S. Kennedy and U.S. Secret Service Agent Helena Harper. There they find out that Sherry's boss, Derek C.Simmons, is the one behind the C-Virus bioterrorist attack. Sherry informs Leon that she is actually supposed to meet up with Simmons in Lanshiang . Before they can finish their conversation they are attacked by the Ustanak and once defeated, the two pairs agree to meet up at the rendezvous point.
When Jake and Sherry finally arrive at the meet-up location, they find Leon and Helena in a face-off against Simmons, who readily admits that he is the one behind the outbreak and explains that he did it in order to maintain both U.S. and global stability. Simmons then proceeds to order his guards to shoot down Leon and Helena. While in cover, Leon asks Jake and Sherry to escape while they settle their personal score with Simmons. They leave, but not before Sherry hands Leon an SD card containing vital research information regarding Jake's antibodies. Jake and Sherry manage to escape, but are captured once again by Neo Umbrella.
July 1, 2013
Jake and Sherry find themselves trapped in Neo Umbrella's underwater facility at the bottom of the ocean. Thanks to a tip from Leon, BSAA agents Chris Redfield and Piers Nivans manage to find the underwater facility and free Jake and Sherry. Before they escape, Chris tells Jake that he not only knew his father, but he is also the one that killed him. Jake, now taken over by his emotions, reflexively pulls out his gun and proceeds to fire a one-off shot at Chris, just barely grazing Chris' face. Before the situation could get anymore intense a massive B.O.W., Haos, awakens from his coccoon. Knowing how vital Jake's blood is, Chris tells Jake and Sherry to escape while him and Piers take on the creature. When trying to escape from the facility, the Ustanak shows up again for a final confrontation with Jake and Sherry. After finally putting down the Ustanak, they are able to escape from the facility.
Some time later, Jake hands over Sherry a sample of his blood and disappears—though dropping his price down to only $50. The BSAA agrees to keep Jake's identity top secret, to insure that nobody comes after him. Thanks to Jake's blood a vaccine for the C-Virus has been distilled, and the outbreak is gradually contained. In the Secret Ending (which is obtained by defeating Ada's campaign) we see that Jake continues the fight against the B.O.W.'s in an underdeveloped country(Somewhere in the Middlie East).
After the deaths of a number of soldiers under Chris' command at least six months prior in Edonia (The actual date being December 24, 2012) Chris left the BSAA and became a drunken wreck, before being convinced by Piers Nivans to come back and finish his mission to end bioterrorism, Chris reluctantly returns to the organization.
Chris Redfield and the BSAA - including Piers - are soon after sent into a war-torn China, around the coastal Chinese city of Lanshiang.
Ada's campaign is unlocked following the completion of the 3 main campaigns and is the only campaign to feature solo play. In Ada's story, it is revealed that the Ada Wong that interacted with Chris Redfield and Piers Nivans was actually a Doppelgänger, a scientist named Carla Radames, and that the real Ada Wong was aiding Leon S. Kennedy and Sherry Birkin while destroying the Neo Umbrella lab in Lanshiang. Although presumed dead, Carla tries one last attack against the real Ada, after having injected herself with a powerful dose of the C-Virus, but is killed. As Leon and Helena battle with Derek Simmons, Ada reaches the lab where her clone was developed and destroys everything. She then receives a call from someone, accepting a new assignment.