Note: the events in this movie take place at the same time during the events in the previous movie "The Bourne Ultimatum", thus making this movie a spin-off to the Bourne trilogy.
Aaron Cross (Jeremy Renner) is a member of Operation Outcome, one of the Department of Defense's black ops programs, which provides its agents with green pills that enhance physical abilities and blue pills that enhance mental abilities. He is given the moniker of "Number Five" and is deployed to Alaska for a training assignment, where he meets another Outcome operative, Number Three (Oscar Isaac). Their exchange is initially intense, as Number Three questions Cross as to why he is two days ahead of schedule for their rendezvous. Cross explains to him that he had to take a shortcut through a mountain ridge after having lost his chems while pursued by wolves, along with the requisite bloodwork he draws on schedule to send back to Outcome for analysis.
Cross' arrival two days early confuses Number Three, as the mountain ridge is generally acknowledged as being extremely difficult trip for agents even when assisted with a program kit, yet Cross has completed the challenge in record time without his kit, a fact that ostensibly irritates Number Three, since it appers that Cross has beat Number Three's unofficial "record". After a further exchange in which Number Three agrees to re-package send some of his bloodwork and label it Cross's, both men call an uneasy, implied truce to their tension. A fast-moving blizzard is on the horizon, and Number Three says Cross can stay an extra day, since he won't be able to get ahead of it, despite his early arrival. While lying in bed that evening, Cross happens to notice a number of carvings done in the woodwork above his head, including one of the name "Jason Bourne".
Meanwhile, Jason Bourne is in New York City exposing Operation Blackbriar and the Treadstone Project, leading to CIA Deputy Director Pamela Landy (Joan Allen) and Operation Blackbriar supervisor Noah Vosen (David Strathairn) being investigated by the FBI. Upon learning of this, CIA Director Ezra Kramer (Scott Glenn), also under investigation, calls Eric Byer (Edward Norton), a retired USAF Colonel responsible for overseeing the CIA's clandestine operations, for help.
To eliminate evidence of the Blackbriar program, Byer decides to eliminate all Outcome assets. He orders new meds distributed to the agents. He learns that both Numbers Three and Five are at the same location, and dispatches a U-CAV drone aircraft to kill both agents. Cross's enhanced hearing picks up a faint echo in the distance, and Cross asks Number Three to confirm what he's just heard. He cannot, but he and Cross decide to split up and survey the area separately. Cross exits the cabin moments before the U-CAV missile deployed by Byer's people hits the cabin and kills Number Three.
Cross travels cross country, trying to hide from the sensors the U-CAV is using to track him. He uses a sniper rifle to shoot the U-CAV down. He realizes that his superiors have ordered his assassination. He removes a tracking device that has been surgically inserted below the skin of his abdomen. He captures a wolf and forces it to swallow the tracking device. Tracking Cross' active signal, Byer orders a second U-CAV to attack and kill Cross. The missile, following the tracking signal carried within the wolf, fires its missile at the wolf, destroying it and the tracking device. Byer mistakenly believes that Cross is dead. He continues to kill the remaining Outcome agents across the globe.
The remaining Outcome assets' are given a new medication, a triangular yellow pills that unknown to them kills them within a few hours. Byer captures one of Outcome's foremost scientists, Dr. Donald Foite (Zeljko Ivanek), chemically brainwashes him, and gives him instructions to shoot and kill the other scientists. He brings a weapon into the Outcome research lab and methodically shoots each of the scientists. Only Dr. Marta Shearing (Rachel Weisz), escapes after Foite commits suicide when security forces enter the lab.
Cross travels to Maryland where the lab is located. He locates a car that has been prepped with hidden, spare license plates, a wallet, and other gear essential to creating a new temporary identify. He drives to the vicinity of Shearing's country home.
After she returns home, Shearing is preparing to leave for Montreal when she is visited by four initially friendly CIA agents with orders to complete the job Foite failed at. One of the visitors informs her that Foite's home was filled with pictures of her and articles of her clothing, giving the appearance that he was obsessing on her. One of them says she is a psychiatrist. She reminds her of her employment contract and tells her that Foite spared her life, which Shearing finds incredulous. One agent finds Shearing's pistol and she orders them to leave. The psychiatrist tells Shearing that they need to verify that she's not a suicide risk when the two agents seize her, apparently trying to make it look as if she's committed suicide.
She is rescued by Cross, who kills all four agents. He convinces her to help him after reminder who he is. Shearing reveals that Cross was genetically modified to retain the benefits of the green pills without need of continuous consumption, a process they call "viraling off". Because he hasn't taken a blue pill in several days, Cross realizes that he will soon lose his mental enhancement. He then coerces Shearing to travel to Manila with him, as the pills are manufactured there, in the hopes of being able to viral off the blue pills in the same manner he did the green.
On the way to Manila, Cross reveals to Shearing that he is actually Kenneth J. Kitsom, a former U.S. Army soldier. He tells her that his recruiter raised his IQ by 12 points to make the minimum required. He explains that if he loses the benefit of the medication it will have a big impact on his intelligence. He said that after he was wounded by an IED during the Iraq War that a cover story was created that he had been killed. He was then offered an opportunity to serve his country in the Outcome program.
In Washington D.C., Byer continues to hunt for Shearing and discovers that she is being helped by Cross. From security intelligence gathered at major transportation hubs across the country, Byer deduces that Cross and Shearing have departed the US and are travelling to Manila, where the pills are manufactured, ostensibly to help Cross attempt to viral off the blue pills. Byers decides to activate Larx-03 (Louis Ozawa Changchien), am Outcome super soldier, who has completed the viralling off process and has been programmed as a lethal and emotionless killer. Larx-03 is deployed to Manila to kill Cross and Shearing while Cross is still presumably weak during the viraling off process. Byer also learns that Landy is expected to face charges for assisting Bourne, while Vosen is expected to be declared innocent and returned to duty.
In Manila, Cross and Shearing arrive at the factory where the pills are produced and Shearing administers the blue-pill viralling off procedure for the blue (intelligence) pill to Cross. Byer contacts the factory's supervisor and orders them to lock Cross and Shearing into the basement, but they escape before Larx arrives. They take shelter in an apartment, where Shearing nurses Cross through his recovery from the viralling off process. Cross experiences flashbacks recalling his recruitment into Outcome under Byer's direction. Delirious, he tells Shearing that he has $40,000 in the lining of his jacket and if anything happens she should take it and leave. Cross tells Shearing she should go home, that she's done enough for him. She holds and comforts him.
The next day, Larx-03 informs the local police of Cross' location and follow them to him, hoping they will flush Cross into the open where Larx can kill him. The police arrive while Shearing is buying medicine. She seems them arrive and warns Cross, who has recovered from the viraling off process. He escapes from the police and rescues Shearing. They steal a motorcycle and escape, pursued by Larx. During a chase through the streets and marketplaces of Manila, Cross is wounded and he wounds Larx in turn. Still chased by Larx, Cross is losing strength from his wound. Shearing kicks Larx-03 on his motorcycle and he crashes into a pillar, killing him instantly. Cross starts to pass out. Shearing guides the motorcycle into a controlled slide and they slide to a stop themselves. Cross and Shearing give a boatman a valuable gold watch they'd taken from the factory where the pills are made. He takes them aboard his boat and they depart for places unknown.