Fans of the TV show Firefly know the history of the characters, but the movie smartly re-introduces us to them without boring the die-hard "browncoaters" out there by opening the picture with a flashback showing how Simon (Sean Maher) rescued his sister River (Summer Glau) from Alliance scientists that were experimenting on her. We also get introduced to a threatening new villain (Chiwetel Ejiofor), who is an assassin/operative working for the Alliance and with orders to hunt down and return Summer to them. It is often said that the measure of any good action picture is how good the villain is, and Serenity gives us a darn good one. He's calm, cool, collective and extremely deadly.

The story of Serenity takes place some months after the TV series ended, with Mal Reynolds (Nathan Fillion) about to set out on another one of his famous heists on a local planet. Both Shepherd Book (Ron Glass) and Inara (Morena Baccarin) are no longer aboard Serenity, but they both will cross paths again with Mal and his crew before the movie is over. Aware of River's psychic abilities, Mal wants her to join him on the heist, so she'll be able to sense any impending trouble. But things don't go as planned when during the heist they are attacked by "Reavers" (zombie like creatures) and Mal and the others must make a high-speed escape on land aboard a floating landspeeder-like transport.

When Mal arrives on another planet to sell the materials gained during the heist, a commercial playing in a bar triggers something in River and she starts attacking everyone. Simon is able to stop her, but the crew soon finds out that the Alliance has used the commercial in the hopes of triggering a response in River and finding out where in the solar system she is…which they now do. Mal must now decide whether it's worth it keeping River and Simon aboard as part of his crew any longer, or if the rest of them would be safer without River around.