In The Girl Who Owned a City, a virus has killed off everyone over twelve. Ten-year-old Lisa Nelson takes on a leadership role, finding stores of food and organizing Grand Avenue for protection against gangs. After the local gang burns down her house, she gets the idea of making a defensible castle, and Lisa leads the way in turning the local high school into her own castle, a new city that she fights to run and keep.

As the novel begins, ten-year-old Lisa is foraging for food in deserted houses nearby. Everyone over twelve has been killed off by a sudden and deadly virus. Lisa lives in her house with her young brother. Her neighbor, Jill Jansen, takes in orphaned young children, and Lisa shares some of her supplies. Food is running out, though, and gangs are beginning to form. Lisa worries about the future.

Lisa finds a stash of supplies at a farmhouse out of town and teaches herself to drive to make a supply run. Her first big load, though, is stolen by a local gang. Lisa decides she must organize the neighborhood for protection and calls a meeting of the kids on her street. She also has an idea to get supplies from a grocery warehouse. At the meeting, Lisa promises to share her ideas and supplies in exchange for the neighborhood forming a militia. The children set up defenses, including watch dogs and booby traps.

Lisa and her neighbor Craig go on a supply run to the warehouse, and while they're gone, the local gang attacks. Their leader, Tom Logan, is hit on the head with a rock from one of the defenses. It's a victory, but it's mostly luck. While Lisa and Todd are away on their next supply run, the gang comes in, loots their house, and burns it down.

Lisa decides that the kids need someplace defensible. She thinks of the old high school and forms a plan to create a castle, a defensible city in the high school. The neighborhood children prepare in secret and one day just seem to disappear from Grand Avenue. No one knows they're inside the high school, working in secret. When their defenses are prepared, they make the city public. Lisa makes a constitution, making it clear that the city belongs to her, and others are free to stay only if they follow the rules. The defenses work, through several gang attacks including two by Tom Logan's gang.

When Tom Logan attacks the third time, he takes over the city. Lisa is hurt and believed killed, but her friends quietly take her away to the farm and care for her. Lisa spends her recovery time planning and preparing to take back her city, with the help of her friends. Meanwhile, the people of the city learn that Lisa is alive and desert Tom to come to the farm. When Lisa sneaks into the city to take Tom hostage, she finds a trap awaiting her, but she is able to berate Tom into giving up his hold on the city. Her city is back, but in future danger from the growing gangs in nearby Chicago.