The crew of the Serenity is getting desperate. They have lain lower and lower to protect their doctor, Simon Tam (Sean Maher), and his telepathic traumatized little sister, River (Summer Glau), from the alliance, whom he rescued her from a year earlier. This has made getting jobs harder and now they are desperate. When they take River on a robbery during which Reavers (humans who have gone crazy and turned into cannibals) attack, Simon decides that its time to leave the crew of the Serenity for his and River's safety. She then mutters "Miranda" and goes berserk and nearly shoots Capt. Malcolm Reynolds (Nathan Fillion), until her brother says the safety word to put her to sleep. Reynolds decides to take them back on board for safety, only now an alliance operative (Chiwetel Ejiofor) is on their tracks and making Reynolds determined to find out what "Miranda" is and what the Alliance is hiding.

In the distant future, Captain Malcolm 'Mal' Reynolds is a renegade former interstellar officer now turned smuggler/rogue whom is the commander of a small spacecraft with a loyal hand-picked crew making up of first mate Zoe Warren; pilot Hoban 'Wash' Washburn; gung-ho grunt Jayne Cobb; engineer Kaylee Frye; fugitives Doctor Simon Tam and his psychic sister River, where they travel the far reaches of space in search of food, money, and anything to live off on.