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In 2045, due to various geopolitical events, many of Earth's cities have become slums; its inhabitants regularly escape into the virtual reality world of the OASIS. Its co-founder, the late James "Anorak" Halliday, announces a contest in which players must find an Easter egg inside a gate that requires three keys hidden in the worlds; the winner to receive full ownership and control of the OASIS. This attracts a number of Gunters ("egg hunters") as well as the video game conglomerate Innovative Online Industries (IOI), headed by their new CEO Nolan Sorrento, who employs researchers of Halliday, as well as top gamers and indentured servants called "Sixers".
In Columbus, Ohio, Wade Watts, an orphaned 17-year-old Gunter, lives with his aunt Alice in the "stacks", makeshift towers of trailer homes, and logs onto the OASIS from a nearby cargo van. His avatar Parzival, and his online friend Aech, a male first-person shooter expert and virtual mechanic, participate in the first quest: a vehicle race across ever-shifting roadways in Manhattan. Parzival befriends a well-known Gunter named Art3mis by saving her from being "zeroed out" by King Kong, which would have wiped her character progression. At Anorak's virtual archives containing video clips reconstructing Halliday's life, Parzival gets an insight from a comment that Halliday made to his former business partner, Ogden Morrow, and on the next race, uncovers an underground shortcut to the finish line to acquire the first key. Aech and Art3mis, as well as players Daito and Sho, soon follow; appearing atop the global scoreboard as the "High Five".
At an OASIS dance club, i-R0k, a mercenary helping Sorrento, overhears Parzival tell Art3mis his real name. Sorrento requests Wade to join IOI, but when he refuses out of distrust, Sorrento and his aide F'Nale Zandor bomb Wade's stack, killing Alice and Wade's neighbors. Wade is taken to a Gunter hideout where he meets Art3mis in reality: Samantha Cook. They discover that Halliday regretted a movie date with a woman named Kira, who later married Morrow. After Parzival wins a coin on a small bet with the archive's curator, the High Five enter a re-creation of The Shining where they traverse a series of frightening events to eventually reach Kira to acquire the second key.
Zandor tracks Wade to the Gunter hideout, but finds only Samantha, who is arrested and made into a Sixer for defaulting on her family's debt. Wade is extracted by the other High Five players—Aech / Helen Harris, Daito / Toshiro, and Sho / Zhou—who have been secretly running their avatars from Helen's postal truck. i-R0k activates a force field around the location of the third key inside a fortress on Planet Doom. After tricking Sorrento into revealing Samantha's location, Wade helps her escape. She hacks Sorrento's station, allowing Wade to recruit OASIS players to join an all-out assault against Sorrento and the Sixers at the fortress. Hiding among the active Sixers, Samantha shuts down the force field. During the battle, the rebels defeat Sorrento's Mechagodzilla and i-R0k, but Parzival zeroes out Samantha's avatar to let her escape IOI in reality.
Parzival and Sho find Sixers lining up to play on an Atari 2600 console, but failing on each game after time expires, even when one of them beats Adventure. Sorrento activates the Cataclyst, which zeroes out everyone on Planet Doom (including himself). However, the curator's coin spares Parzival as an extra life. Parzival deduces that the goal is not to win Adventure but to simply find its own Easter egg, which Parzival completes to reveal the third key. Inside the gate, Anorak presents Parzival a contract; however, Wade declines as it is similar to the one Morrow had signed that dissolved his partnership with Halliday. Anorak transforms into Halliday and affirms Wade's decision to be correct. After showing Parzival a Big Red Button that would shut down the OASIS permanently, Halliday officially awards him the Golden Egg as the winner of the contest.
Sorrento and Zandor are arrested after Aech had sent the police a recording of Sorrento's conversation with Wade that resulted in the bombing. IOI's indentured players are freed from their debts, heavily restructuring the company. The High Five share control of the OASIS, with Wade hiring Morrow, who is revealed to be the archive curator, as a consultant. The OASIS resumes operations, but is shut down on Tuesdays and Thursdays to force people to spend more time in the real world, including Wade and Samantha who have formed a relationship and bought an apartment together.