500 years in the future, Earthlings -- facing overpopulation -- have set out to colonize other planets in a distant galaxy. The resultant government -- known as the Alliance -- has colonized and controls the galaxy's inner planets, but those inhabiting the outer ones revolted, resulting in a bloody civil war.
Now that it's over, former rebel fighter turned opportunistic businessman Captain Malcolm "Mal" Reynolds (NATHAN FILLION) leads his ragtag crew of the Serenity through space, taking whatever odd jobs pay the best. Those in his crew include Zoe (GINA TORRES), his second-in-command, as well as her husband-pilot Wash (ALAN TUDYK). Kaylee (JEWEL STAITE) is the lovelorn engineer, wise-cracks are provided by muscular mercenary Jayne (ADAM BALDWIN), and the crew's doctor is Simon (SEAN MAHER).
He's the catalyst for the crew's next mission. It seems that his younger sister, River (SUMMER GLAU), a reported psychic, is being held by the Alliance that wants something important out of her head. She's resisted their efforts so far and turns out to be quite the pre-programmed martial arts expert after the crew rescues her.
Their actions, however, draw the attention of a steely government agent known only as The Operative (CHIWETEL EJIOFOR) whose sole purpose is to find River and prevent what's hidden in her mind from possibly destroying the Alliance. With the aid of the likes of Mal's love interest and courtesan Inara (MORENA BACCARIN), preacher/philosopher Book (RON GLASS) who gives them sanctuary, and technology and communications guru Mr. Universe (DAVID KRUMHOLTZ), Mal and his crew try to avoid the Operative as well as zombie like creatures known as the Reavers who habitually kill and eat humans.