Todd Hewitt is the only boy left in Prentisstown, a small settlement on New World – an alien planet recently colonized by humans. Todd is within days of his thirteenth birthday, the age at which all Prentisstown boys become men.

Todd has been told all the women and nearly all the men on New World were killed in a war with the Spackle – the planet’s native inhabitants – and that Prentisstown is the last remaining settlement. The Spackle are blamed for the release of the Noise germ, a virus that is purportedly fatal to all women. As a side effect of the virus, the remaining men on New World can hear each other’s (and animals') thoughts in an ever-present “Noise”.

One day Todd and his dog, Manchee, discover a "hole in the Noise" in the swamp. When Todd explains this patch of silence to his adoptive parents, Ben and Cillian, his Noise accidentally projects the discovery to the entire town, forcing Ben and Cillian to accelerate their plan to have Todd escape Prentisstown, which they had been planning for his entire life. Todd reluctantly flees to the swamp with Manchee, where he discovers the source of the hole in the Noise: Viola, a girl whose scout ship crash-landed on New World. Todd, Manchee and Viola are attacked by Aaron, the town preacher, but escape when Aaron is mauled by a crocodile. Aided by a map inside Todd's mother's diary, the three travel towards Farbranch, another settlement.

Hildy, a woman from Farbranch, finds Todd and Viola and reveals that the Noise germ is not fatal and does not affect women at all – no women have Noise. She takes the three to her settlement. At nightfall, Mayor Prentiss and his men arrive and burn down the town, killing all those who will not join their army. Todd, Viola, and Manchee flee for Haven, where a rumoured cure for Noise exists. They also hope to find a transmission tower to contact Viola's people, a second wave of settlers.

After days on the road they are found by Davy, Mayor Prentiss’s son. Todd tries to kill him but is unable to follow through. Instead, he ties Davy up before heading off for Haven with Viola. En route, Todd, Viola and Manchee find a live Spackle. Todd is shocked, believing all Spackle were wiped out in the war. Todd kills the Spackle but instantly regrets it. Aaron finds them, stabs Todd, and kidnaps Viola. Todd pursues Viola and Aaron and, using Manchee as a distraction, attempts to rescue Viola. The plan fails, and Todd and Viola flee on a boat, leaving Manchee behind, who is killed by Aaron. Todd passes out from his wounds.

Days later, Todd wakes up under a care of a doctor in another settlement, where Todd encounters Ben hiding in the outskirts of town. Later, Ben explains the truth: the Noise germ is a natural contagion of the planet, not an attack by the Spackle. Men driven mad by Noise and who resented women’s ability to remain silent murdered all women in Prentisstown. For their crimes, Prentisstown was exiled by New World, and if any men were to leave the town, they would be executed.