[Darrell Lawrence]

Five hundred years in the future, mankind has abandoned Earth and moved en masse to another large star system. National governments no longer exist, and political power instead resides with the interplanetary Alliance government. People on the "central planets" pursue a wealthy and cultured lifestyle and are tightly ruled by the Alliance. In contrast, life on the partially-colonized "outer rim" planets more closely resembles that of the American Old West.

The crew of the cargo ship Serenity ekes out a living in the outer rim, dodging both the Alliance and the savage spacefaring cannibals known as Reavers. Crewmember Simon Tam, who has given up his career as a physician to rescue his sister River from a secret Alliance program to create a unit of psychic warriors, objects when the ship's captain, the emotionally-scarred Malcolm "Mal" Reynolds, takes River along on a bank heist. The job is disrupted by a Reaver attack, but thanks to River's early warning, the team narrowly escapes back to Serenity. Simon, enraged that his sister was put in such danger, declares that they will leave the ship as soon as possible.

The crew disembarks to allow Mal to meet the men who hired them for the heist. River enters the bar where the meeting is taking place and, after watching an advert on a screen, begins assaulting the other patrons. She is only stopped when Simon shouts out a code phrase that, because of River's mental conditioning, causes her to pass out. Mal takes her and her brother back to the ship. The crew contacts a reclusive techno-geek called Mr. Universe, who analyzes the bar's security camera footage and discovers that River's assault was triggered by a subliminal message. Unbeknownst to the crew, the signal was planted by the Operative, a self-described monster with no name, rank, or official existence, who is hunting River and Simon on behalf of the Alliance.

Mal receives a call from Inara Serra, a former passenger, who asks for help with local unrest. Recognizing the request as an Alliance trap, Mal believes that confrontation is necessary to determine what is happening. He goes to her and meets the Operative, who offers to release Mal if he surrenders River. Mal refuses and, after a brief fight with the Operative- which he only escapes from thanks to a distraction planted by Inara- escapes with Inara back to Serenity. River discovers that the source of her inner torment, "Miranda", is an outer rim planet that was deemed uninhabitable and removed from navigational charts. However, traveling there would require passing through Reaver territory, so the crew instead goes to Haven, now home to another former passenger, Shepherd Book. The crew arrives to find Book fatally wounded and the Haven colony destroyed by an Alliance attack. Mal learns that the Alliance has laid waste to all of Serenity's sanctuaries and receives a message from the Operative, who promises more of the same until River is surrendered.

Overriding his crew's protests, Mal has Serenity disguised as a Reaver vessel. They pass through a Reaver spacefleet unscathed and discover that Miranda is habitable, but its cities contain only corpses. The crew finds a transmission from an Alliance officer, which explains that the Alliance attempted to achieve permanent peace on the planet by pumping a drug designed to suppress aggression into the atmosphere. Instead, the drug suppressed the population's motivation to do anything, and they died of starvation. Meanwhile, 0.1% of the population experienced the opposite reaction: they became the first of the hyper-violent Reavers. Mal plans to disseminate this information to the entire system via Mr. Universe's powerful transmitters, but the Operative waits there with a fleet of Alliance ships. Mal anticipates this and during the return trip fires upon a Reaver vessel, which causes the entire Reaver fleet to give chase. Arriving at Mr. Universe's planet, a massive battle between the Alliance and Reavers ensues, which allows Serenity's pilot Wash to fly down to the planet. The Operative follows them in an escape pod after the destruction of his ship in the battle.

Struck by an EMP from a pursuing Reaver ship, Serenity crash-lands on the surface. The crew survives, but then a Reaver harpoon smashes into the ship's cockpit, killing Wash instantly. Fleeing the ship, the crew prepares a last stand against the Reavers to allow Mal sufficient time to transmit the message. Mal finds Mr. Universe murdered and his equipment destroyed, but triggers a message revealing the location of a hidden backup transmitter. The crew at first maintains their defense, but injuries begin to mount, and they retreat behind a blast door. The door fails to close completely, so River dives through the opening and seals it, which leaves her trapped with the Reavers.

Mal and the Operative reach the secondary transmitter and have a final showdown. Mal wins the fight, but he spares the Operative's life, leaving him to watch the broadcast of the Alliance secret. As Mal rejoins the crew, the blast doors reopen to reveal River standing amidst piles of dead Reavers. Alliance troops burst onto the scene and ask the Operative for a kill order. With the Alliance's secret revealed and his personal belief in the Alliance's social engineering methods shattered, he orders the troops to stand down.

The crew buries Mr. Universe, Shepherd Book, and Wash, and patches up Serenity. As the ship prepares to leave, the Operative warns Mal that while the two of them will never meet again, and the Alliance is weakened, "They are not gone, and they are not forgiving." Serenity blasts off with Mal and River sitting at the controls.