In a distant future, humanity has colonized a new star system after Earth became overpopulated and polluted. The central planets formed the Alliance, a powerful authoritarian government that defeated the outer planets' independents who wanted self-rule. Among the survivors of the independents, known as Browncoats, is Captain Malcolm "Mal" Reynolds, who now lives as a small-time smuggler and pirate aboard his ship, Serenity. Mal, along with his eclectic crew including a mercenary, a mechanic, a pilot, a companion, and a young doctor named Simon Tam with his mentally disturbed sister, River. River was subjected to government experiments that enhanced her psychic abilities but fractured her mind.

The crew of Serenity takes on a job that puts them on a collision course with an Alliance operative. This operative is determined to recapture River, as she holds key secrets due to her psychic powers that are potentially damaging to the Alliance. As they are pursued, Mal begins to realize the importance of the information locked within River's mind, leading him to question their way of life and his own understanding of the universe. The crew must navigate a series of dangerous encounters that challenge their loyalties and threaten to tear them apart, all while they learn more about the sinister realities of the Alliance's rule.