In the hills of Appalachia, Pentecostal pastors Jamie Coots and Andrew Hamblin struggle to keep an over-100-year-old tradition alive: the practice of handling deadly snakes in church. Jamie and Andrew believe in a bible passage that suggests a poisonous snakebite will not harm them as long as they are anointed by God's power. If they don't practice the ritual of snake handling, they believe they are destined for hell. The pastors must frequently battle the law, a disapproving society, and even at times their own families to keep their way of life alive.
Concerned about who will replace him should he die from a snake bite, Jamie tries to groom his son, Little Cody, to take over the pastorship. Meanwhile Andrew Hamblin holds a special outdoor service to help save a close friend.