Captain Malcolm 'Mal' Reynolds is a former galactic war veteran who is the captain of the transport ship "Serenity". Mal and his crew, ensign Zoe Alleyne Washburne; Zoe's husband, pilot Hoban 'Wash' Washburne; muscular mercenary Jayne Cobb; young mechanic Kaylee Frye; former Alliance medical officer Simon Tam; his disturbed teenage sister River (both on the run from the interplanetary government "The Alliance"); the beautiful courtesan Inara Serra; and preacher Shepherd Book do any jobs, legal or illegal, they can find as the Serenity crew travels across the outskirts of outer space.
After a flashback to Zoe's and Mal's days in the wars six years previous, we cut to the modern day where the Serenity crew is running a salvage operation on a deserted ship and are forced to flee with the cargo when the Alliance show up. Their buddy Badger refuses to buy the cargo so they head off to the rim worlds after picking up three passengers: Book, Simon, and Dobson. En route someone sends a signal to the Alliance and it turns out to be Dobson, an undercover Federal agent, who arrests Simon but is glad to take the whole crew in. He shoots Kaylee before being captured, and Simon forces Mal to flee in return for his doctoring services. When Mal investigates Simon's cargo he finds a naked woman...
Serenity continues to travel through space conducting illegal runs across the star system, which is under the control of The Alliance. A powerful and fearsome mobster named Adelei Niska demands that the crew of Serenity pull a train robbery. The train is carrying medical supplies for a community, and Reynolds and Zoe get held on suspicion. They get free with Inara's help but realize they were tricked and try to return Niska's money. His henchman isn't too happy, but Mal "persuades" the next guy to take the money back. Meanwhile, two blue-handed, black-suited operatives close in on River.
On a salvage mission aboard a drifting colony ship, the Serenity crew find signs that the crew were killed by the cannibalistic Reavers. They find one survivor, but things take a turn for the worse when an Alliance ship looking for an unspecified Firefly-class ship with brother-and-sister stowaways shows up and takes them in.
On the planet Persephone the crew contact their old "friend" Badger the ruthless crime lord to transport some goods on behalf of a local lord. While at a ball to arrange a transport job with the lord, Mal defends Inara's honor when her current customer insults her. By local custom he unintentionally challenges her date, Atherton Wing, to a duel.
On a planet, Simon is kidnapped by locals who need a doctor, while River is threatened with burning as a witch.
While completing a job on a backwater world, Mal is married to a village girl without his knowledge. The girl, Saffron, gets onboard and the crew does not find her until they're already in the air. Mal is not sure what to do with her, but let her come along.
Serenity sets down at the mudder colony of Canton where it turns out Jayne is a hero for having dropped a bunch of money there years ago that he and his partner Stitch stole from the local magistrate. The drop was unintentional but Jayne doesn't turn down the attentions. Meanwhile, Kaylee and Simon dance, River rewrites Book's bible, and Inara beds the magistrate's son, a virgin.
In a delirious state after Serenity's engine explodes, draining the ship of its oxygen supply, Mal has a series of flashbacks about how he came to own Serenity and form his crew.
The crew visit the planet Ariel because Inara needs to receive an annual Companion physical. The crew is offered a surprising job by Simon: in return for stolen medicine he wants them to get him into a hospital to use a high-end scanner to diagnose River. Simon devises a plan - Kaylee and Wash browse through the local dump and find parts to make an imitation emergency vehicle so the crew can get into the hospital posing as EMTs. Simon and River pose as corpses with the aid of a drug Simon has. While Mal and Zoe round up some medicine, Jayne stays with River and Simon, who are unaware he has ratted them out to the Alliance in return for money.
Jayne rushes Simon through the examination and on the way out Jayne, Simon, and River are caught by the Alliance. Jayne is betrayed by the Alliance and becomes a prisoner himself. They manage to escape as the Men With Blue Hands arrive and ruthlessly execute anyone who had contact with the Tams. Mal and Zoe end up saving their friends and Simon ma
Jealous of Zoe's relationship with Mal, Wash insists (thanks to a bit of scheming) that he go with Mal to try to sell some of the medical supplies the crew stole from the Alliance. In the middle of the deal Mal and Wash are kidnapped by men working for Niska the crime lord, who wants revenge against Mal for the botched train heist. He tortures Mal and Wash until Zoe shows up offering money in exchange for the prisoners. Niska says that the money is only enough for one person and Zoe chooses Wash. Wash realizes that Mal's antagonizing him while they were being tortured was to help keep him alive and kicking. This inspires him to do everything he can to help Zoe rescue Mal from Niska. The rest of the crew jump on board to save the Captain.
Meanwhile Inara extends her services to a council member. To the crew of Serenity's surprise, it's a woman. And Simon continues to treat River with some of the medicine he stole but she suffers the occasional relapse as well as displays a penchan
Saffron (from "Our Mrs. Reynolds") returns - after Mal breaks up her current gig, she convinces him and the crew to help out with a ""perfect crime"" that isn't. The crime: go to Bellerophon and steal a criminal's prototype laser gun from his collection. The plan: Saffron and Mal sneak in and dump the gun down the trash, bypassing security, and the Serenity crew grab it from the disposal system. Of course, this is Saffron, and it turns out she's married to the crook, Durran, and plans to double-cross Mal. Things don't work out so well and Saffron strands Mal naked in the desert. Fortunately Mal and Inara anticipated a betrayal and set it up so Inara grabs the gun, leaves Saffron behind, and rescues Mal.
Meanwhile, Simon figures out Jayne betrayed them (in "Ariel") and the two have words.
An old war comrade of Mal's and Zoe's, Tracey, mails his corpse to them. He also leaves a message asking them to deliver his body to his family. Some men claiming to be with the Alliance is on the trail of the body and catch up to them demanding the body. The crew can't find anything on Tracey's corpse, but as they prepare to cut it open, Tracey comes back to life. He explains he is smuggling super-organs in his own body. They flee to the planet with the men in hot pursuit and eventually/supposedly agree to give up Tracey. Tracey gets wind of the plan and makes a break for it with Kaylee as a hostage, they shoot him down and Mal reveals they were going to send the officer off since he's out of his jurisdiction and on a personal mission with no authority. Then Tracey dies and they deliver his body for real this time.
The crew of the Serenity are in for a gunfight when one of Inara's companion colleagues asks for their help. The Serenity crew defends a bordello from a gunslinger who got a prostitute pregnant and now intends to collect the child; Mal falls for the bordello's madam.