In the 26th century, humanity has left an overpopulated and decimated Earth and moved to a new star system, colonizing many planets and moons. The central planets are ruled by an Alliance that has won a war against the Colonies, less established planets in the new outer solar system. The colonies refuse to accept the Alliance rules & are at war.A young girl named River Tam (Summer Glau) is the most promising of a number of young people being mentally and physically conditioned against their will by Alliance scientists. The Alliance wants to use these kids as weapons against the colonials. River was actually a colonial herself, being used by Alliance to fight against her own people.Rescued by her brother Simon (Sean Maher), the two find refuge aboard the Firefly-class transport ship Serenity, captained by gun-for-hire Malcolm "Mal" Reynolds (Nathan Fillion), a colonial veteran. An Alliance agent, the Operative, is charged with finding and killing River, as high Alliance politicians have accidentally exposed top secrets to her psychic abilities. Aboard Serenity, Mal takes River along on a bank robbery (As River is a psychic & Mal can use her to know about events before they happen), against her brother's objections. Simon is the resident physician aboard the Serenity. Kaylee is the engine mechanic.They are attacked by Reavers, wildly savage humans who eat their victims alive. They escape, but Simon decides that he and River will leave Serenity at the next port called Haven. While Mal meets fences Fanty and Mingo at a bar to sell the bank robbery loot, a TV commercial causes River to attack the patrons with effective martial arts. Just before she can shoot Mal, Simon arrives and shouts a "safe word" which causes her to fall asleep. Mal carries River back to Serenity, but the incident is captured on camera. The crew contacts a reclusive hacker known as Mr. Universe who analyzes the commercial and discovers a subliminal message being broadcast across Alliance space designed specifically to trigger River. He notes that River whispered "Miranda" before attacking.While hiding out on Haven, a mining colony and home of Shepherd Book, Mal receives a call from Inara, a former passenger, offering work. Suspecting a trap but fearing she is in danger; Mal goes to her sanctuary and is confronted by the Operative. He promises to let Mal go free if he turns River over, but he refuses and, thanks to Inara's quick thinking, she and Mal escape. After another of River's outbursts, the crew discover that Miranda is a remote planet that had become uninhabitable because of an Alliance meddling. Serenity returns to Haven while the crew ponder their next move. They discover that the outpost has been destroyed and the residents slaughtered. They then learn The Operative is killing all of Mal's contacts to deny him a safe haven. He promises that he will pursue them until he gets River. Mal decides to travel to Miranda to see if he can learn the truth of the situation.Inara fears the Operative as she thinks of him as a believer in the Alliance's cause. She knows that the Operative believes that it is best for River to die for the greater good of the Alliance, which the Operative believes to be working for the forces of good.The route to Miranda is blocked by a region swarming with Reavers, so Mal disguises Serenity as a Reaver ship (an act that his first mate, Zoe (Gina Torres), strongly protests). After sailing through a fleet of Reaver vessels, the crew discovers a habitable planet with cities filled with mummified corpses. They discover a recording by an Alliance survey team explaining that an experimental chemical, designed to suppress aggression in the residents, was introduced into the air processing system. The agent worked too well, and the colonists literally lost all emotional drive, eventually starving in droves when they lost interest in basic survival. However, one person in a thousand had an opposite reaction and became what was now known as the hyper-aggressive and unstable Reavers. So, the Alliance experiment was responsible for the greatest threat facing humanity in the universe today.Mal contacts Mr. Universe to arrange to have the log broadcast to the solar system to get the colonials to re-energize & fight for the new solar system, but the Operative is already there and has Mr. Universe lure them in, before mortally wounding him. Mal suspects Serenity is heading into a trap, so while traveling back through Reaver space, he opens fire on one of their ships. The Reavers pursue Serenity to Mr. Universe's planet, where they stumble upon the waiting Alliance fleet and begin fighting. The Operative's ship is destroyed, but he uses an escape pod. Serenity is damaged by a pursuing Reaver ship but manages to crash land.Shortly after the crash, Hoban "Wash" Washburne is killed by Reavers that attack the ship, and the crew flees. Finding Mr. Universe dead and his equipment wrecked, Mal learns of a secret backup transmitter from a message recorded by the dying Mr. Universe. The crew makes a stand against the Reavers to buy Mal the time to send the message. After a firefight, the crew retreat behind a set of blast doors, but the doors only partially close. Zoe and Kaylee are wounded. Simon discovers he has left his medical kit behind; as he rises to retrieve it, he is shot. He apologizes to River for failing her. She replies that it is her turn to take care of him. She charges through the opening in the blast doors, triggers the closing mechanism and throws the medical kit through the opening before the Reavers drag her away.Mal reaches the transmitter, but The Operative is close behind. In hand-to-hand combat, Mal manages to disable his opponent and bind him to a railing, forcing him to watch the recording. Mal returns to his crew. The blast doors open to reveal that River has dispatched all of the Reavers. The wall behind her explodes, and Alliance troops rush in. The Operative recognizes his defeat and that his vision of a 'better world' is inherently flawed and orders his men to stand down.After the crew erect memorials to their deceased friends on Mr. Universe's moon, they patch up Serenity. Kaylee and Simon consummate their relationship. The disillusioned Operative tells Mal that the Alliance government has been weakened and that he will try his best to present his former foe in the best light but cannot guarantee that others will not be sent after Mal and his crew. Serenity lifts off with River as Mal's new copilot.