Hack//Quarantine is the fourth of a series of four games, titled . hack//Infection, . hack//Mutation, . hack//Outbreak, and . hack//Quarantine, features a "game within a game"; a fictional massively multiplayer online role-playing game (MMORPG) called The World which does not require the player to connect to the Internet. Players may transfer their characters and data between games in the series. Each game comes with an extra DVD containing an episode of . hack//Liminality, the accompanying original video animation series which details fictional events that occur concurrently with the games. The games are part of a multimedia franchise called Project . hack which explores the mysterious origins of The World. Set after the events of the anime series . hack//Sign, the games focus on a player named Kite and his quest to discover why some users have become comatose as a result of playing The World. The search evolves into a deeper investigation of The World and its effects on the stability of the Internet.

Fresh off the victory against Gorre, Kite finds Elk still searching for Mia. Kite has no information, so Elk continues his search. Kite then moves on to the newly opened Ω Server to discuss the next move, but the server crashes, forcing Helba to connect everyone to her mirror server. Helba's server has all the same functions, except the server looks like Net Slum. Now that they are relatively safe, Helba says that the Wave is still moving and that she will work on a vaccine to defeat it. Lios then orders Kite to measure data fluctuations by going to Ω Bigoted Snowflake's Capsule. Shortly after getting the data for Lios, it is reported that the Nizato University Hospital, the place Yasuhiko is being hospitalized in, suffered a blackout. Kite does not have much time left. Luckily, he gets another clue from Net Slum resident Spiritas, who tells him of Harald having something to do with Σ Screaming Wind Sand's Fate Castle. At the bottom is yet another room, this time with a lone tree at sunset and another Epitaph fragment.