Silence tells the story of Sebastion Rodrigues, a young Jesuit priest in Portugal. In 1637, he sets out for Japan alongside two priest companions. They plan to go to Japan both to do missionary work and to find out the truth about their teacher, Christovao Ferreira, a well-respected missionary and theologian in Japan who has recently been shamed because of his apostasy. In Japan, the Christians live under heavy persecution and are often tortured into apostasy.
In Macao, Rodrigues and his companion Garrpe make the acquaintance of Kichijiro, a Japanese man who knows Christians that practice their faith in secret. He is shifty and an alcoholic, but the best choice for a guide that Garrpe and Rodrigues have. They arrive in Japan in a small town called Tomogi, near Nagasaki. Here Rodrigues and Garrpe administer their faith from a secret hut high up a hill. Things go tolerably well, if cold and hungry, for a while. But soon Rodrigues's faith is test: two Christians from the village, when asked to apostatize, refuse. They are then left in the ocean on stakes to die of exhaustion. Rodrigues begins to question why God is silent in the face of this horrible suffering of his followers.
Garrpe and Rodrigues part ways. While Rodrigues is trekking through mountainous villages, he happens upon Kichijiro, who escaped death alongside the two Japanese Christians by apostatizing. He begs for forgiveness for his weakness, which Rodrigues reluctantly grants. Soon thereafter he betrays Rodrigues by turning him over the Christian-hunting officials. Rodrigues is jailed along with several Japanese Christians. He meets with an interpreter who urges him to apostatize, but Rodrigues refuses. Rodrigues is taken to another prison.
There he meets Inoue, the local magistrate, who is much feared for his gruesome torture methods. Inoue appears to be a kindly old man who tries to convince Rodrigues to apostatize because the Christianity of Japan can never put down solid roots; he claims that the land is fundamentally inhospitable to the religion. Still Rodrigues will not apostatize. When one of the Christians is murdered for not apostatizing, Rodrigues again questions why God has not stepped forward.
The remaining Christians in the village are taken out to sea and drowned for not apostatizing. Garrpe, who has reappeared, tries to save them but drowns. In his head, Rodrigues contemplates telling Garrpe to apostatize to save them, but cannot bring himself to say it. He is once more horrified by God's silence at this massacre. Rodrigues falls into a deep depression, and eventually is taken to meet Ferreira. Ferreira has apostatized and is in fact writing a book refuting Christianity. He too tells Rodrigues to apostatize.
Ultimately Rodrigues does apostatize. He is taken to a dank prison, and in the night he hears the moaning of Christians in "the pit," a brutal torture method. Ferreira visits him and tells him that he himself spent three days in the pit, and apostatized because God did nothing to help the other victims. The next morning, after Christ speaks to Rodrigues and tells him to trample on his face, Rodrigues successfully apostatizes.
Afterward he is confined to a certain home for a while until Inoue figures out what to do with him. Ultimately he is sent to Edo to assume the name, property, and wife of a dead man. There he lives out the rest of his days, dying at the age of 64. The last two chapters of the book are written from the perspective of a young Dutch clerk in Nagasaki and a diary of a member of Rodrigues's household when he is older.