Silence is the story of the Japanese persecution of Christians that occurred in the 1600s. More specifically, Endo traces the life of Sebastian Rodrigues, a Portuguese missionary from the Society of Jesus, as he tries to survive as a Christian priest working in Japan. Rodrigues and two of his friends journey to Macao, China. They hope togain entrance into Japan in order to locate their former teacher, Christovao Ferreira. Ferreira has been working in Japan for over thirty years; but correspondence from the priest abruptly ceased, and only a few tales of how Ferreira apostatized following several torturous days suspended in the pit tell what happened.

Rodrigues, Francisco Garrpe, and Juan de Santa Marta gain permission from their Superiors in Portugal to make the journey from Lisbon to Macao. However, once the three priests land in China, they are informed that all Portuguese ships from Macao to Japan have been prohibited. Valignano, the administrator for the Society of Jesus working in Macao, forbids the priests from continuing their journey. After much discussion the priests obtain Valignano's permission to secure a Chinese ship and continue on to Japan. Santa Marta is deemed too ill to travel, and so only Rodrigues and Garrpe arrive in Tomogi, Japan. Their contact, Kichijiro, locates a group of Christian peasants willing to hide the priests in a charcoal hut just outside their village.

The priests have little contact with other villages and learn nothing about the fate of Ferreira. One day, officials come to the village looking for hidden Christian items. Garrpe and Rodrigues decide that it would be best for everyone if they separate and leave the village. Rodrigues sails across the sea but fails to find another village to hide in. As he struggles across the mountains he encounters Kichijiro, who has been trailing the priest for some time. Kichijiro promises to take Rodrigues to another safe village; but after several days of walking the priest is captured by officials.

Rodrigues is shifted between various holding huts before landing in a prison cell outside of Nagasaki, Japan. Nagasaki is the traditional seat of the magistrate, Inoue, who is responsible for the interrogation and torture of all captured Christians. Rodrigues knows of several priests who have apostatized following being suspended in "the pit" and figures that it is only a matter of time before he too is subjected to severe torture. The time in prison and the treatment of other prisoners forces Rodrigues to reflect on his own faith.

He draws parallels between himself and Christ as he is betrayed by Judas, persecuted by the Jews, and finally nailed to a cross. For most of the book Rodrigues feels that God has chosen to be silent about the suffering of His people. It is not until the very final chapter that Rodrigues comes to terms with God and all the events that have happened to him in Japan.