Reamde begins by introducing two members of the Forthrast family who reconnect at an annual family reunion: Richard "Dodge" Forthrast, a middle-aged man who is the second of the three Forthrast sons (John, Richard, and Jake), and Zula Forthrast, John's adopted Eritrean daughter, Richard's niece.
Richard is described as "notable enough to merit a contentious Wikipedia entry", having achieved fame and a net worth of nearly one billion dollars by founding a company that designed and operates an MMORPG called "T'Rain". T'Rain is a fantasy-themed virtual world with an extensive mythological backstory, incorporating an economic system intentionally geared towards meeting the needs of conventional players as well as gold farmers, who specialize in converting in-game currency to actual hard currency.
Richard also owns a cat skiing resort in British Columbia, and his chequered past includes having been a marijuana smuggler. Richard decides to offer Zula a job at his company.
Zula and her boyfriend, Peter, visit both the reunion and Richard's resort, located near the US–Canadian border where Richard used to run drugs. Desperate for money, Peter sells a database of stolen credit card numbers to a shady contact. The transaction results in a ransomware virus infecting the deal broker's laptop, which contains the only copy of the database.
The virus, named "REAMDE", affects T'Rain players by encrypting any seemingly valuable files and extorting in-game gold in exchange for a key to decrypt those files. As a consequence of the in-game payment method, chaos has already been building in the virtual world around the region holding the ransom drop points.
Peter, Zula, and the middleman attempt to comply but take too long, and the middleman's ultimate client, the Russian mob, with the assistance of their own IT support, manage to find them in Seattle. After their predicament is explained, Ivanov, the gangster, notes the middleman has compromised too much of the criminal organization's activities, murders him (or pretends to) in Peter's loft, and takes Peter and Zula hostage. Ivanov has been quietly siphoning common funds for risky profit schemes and is trying to save face before his associates punish him for his losses. With information Zula obtains from her employer, they travel to Xiamen, PRC, to track down those behind Reamde and kill them.
Upon arriving in China, Peter, Zula, Csongor, who is a Hungarian hacker offering the mafia IT support, and Sokolov, a former Spetsnaz security consultant hired by Ivanov, search the city for Reamde's perpetrators, eventually locating their apartment. The Russian security team prepares to raid the gold farming team, composed of young Chinese men, only to be misdirected by Zula into a random apartment, which coincidentally happens to house Islamic terrorists preparing to bomb an international conference soon to take place in the city.
Ivanov murders Peter, and Abdallah Jones, a black Welshman who is the head of the cell and a highly wanted man by the UK's MI6, murders Ivanov following a highly destructive battle within the building. The gold farmers flee the building as a fire sets off the stored explosives and causes it to collapse. Jones proceeds to flee, kidnapping Zula as he goes.
This crucial turning point in the plot also introduces Olivia, an MI6 agent who located and was gathering intelligence on the elusive Jones in anticipation of assassinating him. The story separates into four main threads at this juncture: Zula and Jones as they flee from the scene; Olivia and Sokolov as both attempt to extract themselves from their illegal presence in China; Csongor, Marlon, the lead author of the Reamde virus scam, and Yuxia, a local Hakka woman caught up by chance as the Russian's guide and driver, as they attempt to rescue Zula; and Richard as he continues to deal with the fallout of Reamde.
Jones hijacks a taxi that takes him and Zula to a dock where some of Jones' network take them aboard a boat. Csongor comes close to killing Jones but fails, while Yuxia is taken captive for her part in the attempt. Jones' men sail to an airport where he coerces Zula into helping hijack the private jet that first brought her and the Russians to China. The jet's pilots are pressed into service, flying everybody off-radar and into the snowy wilderness of Canada, where they are killed. Zula reveals her relation to Richard to keep herself alive, and Jones continues to drag her around as Canadian terrorist cells are called upon to join with him. Several civilians are murdered for their vehicles as more passably Western cell members are brought in for what will ultimately be a major attack on the Las Vegas Valley, once the US border can be crossed. They aim for Richard's resort and use Zula as leverage to gain his assistance crossing into Idaho.
Csongor and Marlon buy a boat and try to chase after Jones and rescue Yuxia. They make their move on the terrorist trawler after Jones and Zula have left but manage to save Yuxia and kill all of the terrorists on board. They then have to learn how to sail, running out of gasoline, until they find themselves in the Philippines, making their way to a modern city where Marlon can begin to assemble his T'Rain crew to start picking up all of the Reamde extortion money and use it to assist the three of them as they try to figure out where to go next.
Sokolov, hoping to kill Jones and save Zula, tracks down Olivia after their brief encounter in the immediate aftermath of the apartment battle, chancing across her spy equipment and wallet, and offers her assistance in getting out of China. Through Zula, Jones knows where to find Sokolov, but Sokolov kills those sent to kill him and, as they've found Olivia's address, goes back to find her and kill her attackers as well. He lets Jones know he's still alive and warns him not to harm Zula. He and Olivia swim to Taiwanese territory, where they become intimate before she locates a nearby handler. The handler's promises to get them both out in exchange for intelligence on Jones fail to materialize as a hit squad attempts to kill Sokolov as he departs. He escapes, though Olivia thinks he's been killed. Olivia is tasked with further Jones-related work, heading first to the Philippines to meet the last main character to be introduced, Seamus Costello, a CIA operative responsible for Jones-related work solely in the Philippines. They find it unlikely he is there, and Olivia heads for the US as a secondary hypothesis on where Jones has gone. Olivia meets Richard to dissuade him from going to China to look for his niece as she now knows everybody is long gone.
Seamus remains in the Philippines, so when the T'Rain administrators pick up on Marlon's login to the game, he finds the trio in an internet cafe and helps bring the three of them, without homes and newly rich, to the US to gain new identities.
Richard is also dealing with the virus and trying to integrate a player-originated schism deviating from hard-coded good and evil character assignments to color-based alignments, the brightly colored graphical character palettes against more neutral earth-toned colors, corresponding roughly to stark versus nuanced points of view. A major force behind the realignment originates in the writings of the two principal authors of T'Rain's narrative, one a Cambridge don who writes highly regarded fantasy, the other a pulp author who churns out volumes of poorly regarded fantasy. To provide more balance to the so-called War of Realignment, a new narrative is derived to incorporate Reamde and make sure some of the extorted money ends up in the hands of the numerically weaker earth-toned side.
For various reasons, all of the characters begin to converge on the resort and its US-side counterpart where Richard's youngest brother Jake lives with a community of Christian isolationists and second amendment fanatics. The terrorists find a location near the resort to camp and inform Richard, who is directing Reamde triage alone at the resort, of their hostage, forcing him to lead them into the US while a small team detonates a suicide bomb near the border as a distraction. Seamus brings the three new Americans to Idaho on a hunch shared with Olivia, who has chanced upon Sokolov in the US and also brought him to Idaho.
After being used as bait, Zula manages to escape from a skeleton crew that was readying to kill her, gathering supplies from the resort before heading out to rescue her uncle. US terrorist cells also converge on the Idaho property, and protagonists and terrorists end up battling one another in a terrific gunfight around Jake's home, demolishing it. In the end, Richard kills Jones.
Richard's oldest brother John is killed during the firefight while others receive various levels of injury. Zula and Csongor, Olivia and Sokolov, and Seamus and Yuxia end up in relationships as the story closes at the next Forthrast family reunion.