An expedition from Straumli Realm, an ambitious young human civilization in the high Beyond, investigates a five-billion-year-old data archive in the low Transcend that offers the possibility of unimaginable riches. The expedition's facility, High Lab, is gradually compromised by a dormant superintelligence within the archive later known as the Blight. However, shortly before the Blight's final, "flowering", two self-aware entities created similarly to the Blight plot to aid the humans before the Blight can escape.
Recognizing the danger of what they have awakened, the researchers at High Lab attempt to flee in two ships, one carrying all the adults and the second carrying all the children in "coldsleep boxes". Suspicious, the Blight discovers that the first ships contains a data storage device in its cargo manifest; assuming it contains information that could harm it, the Blight destroys the ship. The second ship escapes. The Blight assumes that it is no threat, but later realizes that it is actually carrying away a "countermeasure" against it.
The ship lands on a distant planet with a medieval-level civilization of dog-like creatures, dubbed "Tines", who live in packs as group minds. Upon landing, however, the two surviving adults are ambushed and killed by Tine fanatics known as Flenserists, in whose realm they have landed. The Flenserists capture a young boy named Jefri Olsndot and his wounded sister, Johanna. While Jefri is taken deeper into Flenserist territory, Johanna is rescued by Tine pilgrims who witnessed the ambush and deliver her to a neighboring kingdom ruled by a Tine named Woodcarver. The Flenserists tell Jefri that Johanna had been killed by Woodcarver and exploit him in order to develop advanced technology (such as cannon and radio communication), while Johanna and the knowledge stored in her "dataset" device help Woodcarver rapidly develop in turn.
A distress signal from the sleeper ship eventually reaches "Relay", a major node in the galactic communications network. A benign transcendent entity named "Old One" contacts Relay, seeking information about the Blight and the humans who released it, and reconstitutes a human man named Pham Nuwen from an old wreck to act as its agent, using his doubt of his own memory's veracity to bend him to the Old One's will. Ravna Bergsndot, the only human Relay employee, traces the sleeper ship's signal to the Tines world and persuades her employer to investigate what the human ship took from High Lab, contracting the merchant vessel Out of Band II , owned by two sentient plant Skroderiders, Blueshell and Greenstalk, to transport them.
Before the mission is launched, the Blight attacks Relay and concurrently kills Old One. As Old One dies, it downloads what information it can into Pham to defeat the Blight, and Pham and Ravna barely escape Relay's destruction in the Out of Band II .
The Blight expands, taking over races and "rewriting" their people to become its agents, murdering several other Powers, and seizing other archives in the Beyond, looking for what was taken. It finally realizes where the danger truly lies and sends a hastily assembled fleet in pursuit of the Out of Band II .
The humans arrive at the Tines homeworld and ally with Woodcarver to defeat the Flenserists. Pham initiates Countermeasure, which extends the Slow Zone by thousands of light years, enveloping the Blight at the cost of wrecking thousands of uninvolved civilizations and causing trillions of deaths. The humans are stranded on the Tines world, now in the depths of the "Slow Zone". Activating the countermeasure costs Pham his life, but just before Pham dies, he realizes that, although his body is a reconstruction, his memories are real. Vinge expands on Pham's backstory in A Deepness in the Sky .