The Poisonwood Bible, told through the voices of Orleanna Price and her four daughters, is the story of a missionary family who travel to Africa just as the Congo is on the brink of civil war. The family struggles to adapt to their new surroundings while Nathan Price remains oblivious to his family and to the villagers he is trying to convert. Mirroring the conflict in the Congo, the family begins to disintegrate. Although the family is told to leave, Nathan refuses, putting his family in danger. The final straw comes when Ruth May is killed by a green mamba snake placed in their chicken house by a villager. Orleanna and her three remaining daughters walk out of the village and Nathan's life. The women struggle to come to terms with their time in the Congo and their relationships to one another as the years pass.

In 1959, Nathan Price takes his wife, Orleanna, and his four daughters, Rachel, Leah, Adah, and Ruth May, to the Belgian Congo with him to serve as missionaries. Arriving in the village of Kilanga, the family struggles to adapt. Nathan tries to bring together his missionary vision with his racial ideologies and religious superiority. He fails to see the effect that his decision to come to the Congo has wrought on his family and steadfastly refuses to discuss leaving. Rachel, the oldest daughter, is on the brink of woman-hood. She is self-centered and vain. Leah and Adah, the twins, are marked by Adah's disability which formed in the womb. Ruth May, the youngest, views the Congo with a vivid imagination and curiosity.

Amid political events, including independence from Belgium, the first prime minister's murder, and western intervention for economic purposes, the family also experiences turmoil. The Prices are told to leave the Congo for their own safety, but Nathan refuses, saying that they must stay until a replacement arrives even though there is no plan for a replacement. Ruth May contracts malaria and Orleanna falls into a deep depression. As Nathan continues to push for the baptism and conversion of the villagers, the leaders become more and more opposed to his mission. One of them places a green mamba snake in the family's chicken house. It bites Ruth May and she dies almost instantly.

In the wake of Ruth May's death, Orleanna walks out of the village, her daughters trailing behind, leaving Nathan and the village. Their paths over the next decades diverge, as the women try to come to grips with what happened. Leah remains in the Congo and marries an African schoolteacher, Anatole. Rachel flies from the Congo to South Africa, where she eventually ends up owning and running a hotel. Adah returns to the United States with Orleanna and attends medical school. Although the daughters try to reconnect at different junctures of their lives, they are kept apart by their own prejudices and their conceptions of their personal responsibility of what happened in the Congo.