On board the Serenity is River, whom the Alliance performed experiments on, giving her skills like being an incredible shot and martial arts skills. They also damaged her psyche. Mal, captain of the Serenity, is using her skills as they perform their less-than-legal jobs across the universe. During one of these jobs, River attacks without warning and then whispers the word "Miranda."
A hacker contact tells the Serenity crew that the Alliance is broadcasting a message to River activating River's outbursts. They conclude "Miranda" must be connected to the message and discover there was an Alliance colony named Miranda.
On their way to the colony, Serenity runs into Reavers, a group of humans who live on the outskirts of space and are somewhat akin to space zombies.The Alliance government denies their existence. The Miranda colony is deserted, except for dead bodies. A log is found explaining that Miranda was the site of human experiments by the Alliance designed to suppress aggression. Instead it made most of the population slowly lose the will to live, and they died of dehydration. The remainder had a different reaction to the chemicals and became the Reavers.
The film ends with a battle between Serenity, the Reavers, and the Alliance. The Alliance is forced to officially acknowledge the existence of the Reavers. The Serenity crew suffers heavy losses.