Juni Cortez (Daryl Sabara), after stopping Donnagon from activating the EMP device, has retired from the OSS, no longer wanting to work. He now lives a quiet life and works as a private detective, although his salary is very little. One day, he is contacted by President Devlin (George Clooney), former head of OSS, who informs him that his sister, Carmen Cortez (Alexa Vega), is missing after a mission gone wrong. Upset about this, Juni returns to the OSS to learn more about his sister.
Arriving at the technological and computer part of the OSS, he is reunited with Donnagon Giggles (now reformed) and his wife Francesca (Salma Hayek), who explain that Carmen was captured by the Toymaker (Sylvester Stallone), a former OSS informant. The Toymaker was imprisoned in cyberspace by the OSS, but he has since created Game Over, a virtual reality-based video game which he intends on using to escape cyberspace via players that reach Level 5, which is unwinnable. Juni agrees to venture into the game, save Carmen, and shut down the game, given only 12 hours to win. He is also informed that his sister was last seen on Level 4.
In the game, which takes place in a full 3D environment, Juni finds the challenges difficult, having only 9 lives within the game and already losing one at the start. While roaming a cartoon-like medieval village, he finds three beta-testers, Francis (Bobby Edner), Arnold (Ryan Pinkston) and Rez (Robert Vito), who provide him with a passage to the Moon and launch him into space, but mostly to get rid of the competition.
Juni lands on the Moon, losing another life at the process, and receives an opportunity to bring in a fellow ally to assist him, selecting his wheelchair-bound grandfather Valentin (Ricardo Montalb