The Thousand Autumns of Jacob de Zoet opens with an unpleasantly graphic scene of Orito, a Japanese midwife, delivering a stillborn baby from a person of power. Contrary to expectations, this child has no bearing on the rest of the plot; the scene occurs rather by way of an introduction to Orito's character.
After this brief introduction, the action switches gears to follow Jacob de Zoet, a young Dutch clerk on a ship bound for Dejima, a tiny Dutch trading island right off the coast of Nagasaki, Japan. The red-headed clerk, a devout Christian, is headed there to make his fortune working under Chief Vorstenbach as the Dutch East Indies Company trades with Japan, in an effort to earn enough money to marry his betrothed, Anna, whose father wants to see Jacob financially stable before marrying his daughter. On the ship before reaching Dejima, Jacob witnesses Chief Vorstenbach deliver justice to Acting-Chief Daniel Snitker, who had been using his position for illicit gain via smuggling. Jacob believes that their arrival will herald the dawn of a new age of honesty in the trade business, ferreting out the corrupt and replacing them with the ethical. His expectations, however, prove unfounded.
This novel is far too long and dense to summarize every plot point. On a grand scale, there is a general three-act structure, the first of which takes up approximately half of the book. In this stage, Jacob de Zoet settles into his life on Dejima. He begins his duties in the Dutch East Indies Comapny, which include scouring previous record logs to find discrepancies and root out the corrupt Dutch officials who may still be working on the island. This, of course, does not endear him to the other members of the company, who initially distrust him as a 'rat.' These other workers include Arete Grote (who seems to do nothing but 'arrange' things and act as a courier), Ponte Ouwehand (a junior clerk), Peter Fischer (an ill-tempered, corrupt clerk who sees Jacob as his rival), Melchior van Cleef (a somewhat more capable but still immoral deputy), and other, less important characters such as Ivo Oost and Baert. On the Dutch side of things, the hierarchy is headed by Magistrate Shiroyama, under whom fall the two main interpreters, Interpreter Kobayashi and Ogawa Uzaemon (the latter of whom acquires more significance as the novel progresses). Jacob also has his first encounter with the Lord Abbot Enomoto, a shadowy figure of authority who strikes Jacob as being somehow off.
It is also during this introductory stage of the book that Jacob encounters Orito, who along with being a midwife is a talented student, and the only female, at the medical academy led by Dr. Marinus. Seemingly remembering Anna only as dimly as a distant dream, Jacob's thoughts become mostly occupied with Orito, whose facial disfigurement (the result of a burn) limits her suitability for marriage. Dr. Marinus also becomes an important, although grouchy, figure in Jacob's life; the two start to form a sort of begrudging and unfriendly relationship that still contains some mutual respect. Jacob's Psalter, his family Christian relic, was confiscated by the interpreters at the border, and if it is discovered, he will be deported at the least, tortured and executed at the worst, due to Japan's strict anti-Christian laws. The interpreter, Ogawa Uzaemon, however, exhibits mercy and keeps Jacob's Psalter a secret, and the two form a bond of friendship as Jacob explains the economic ideas of Adam Smith to help with Uzaemon's translation. With regard to Jacob's crusade for honesty in the Dutch company, it seems that Vorstenbach only outed Snitker to make an example; he's just as crooked as the last chief, and he punishes Jacob for not signing a forged document by forcing him to remain on the island for longer than his allotted time.
The second act of the book still contains elements of the first, but the pace is dramatically increased. Orito is taken to live at the Mount Shiranui Shrine, a nunnery run by Abbot Enomoto with murky intentions; no one really knows the details of what goes on up there. Jacob is unable to intervene and save her, although he does propose marriage to her before she is taken – if she had accepted, she would be legally allowed to remain on Dejima with him. As it happens, however, she is taken to the shrine. A monk from Enomoto's monastery escapes and brings a scroll detailing the atrocities that go on at Mount Shiranui, which are horrific: it appears that the women at the Shrine are raped by the monks, and the babies are killed and sacrificed by the dark cult of Enomoto, who uses their lifeblood to attain immortality. The women of the Shrine, however, believe that their children are living wonderful lives down in the city, and the monks go to elaborate measures to ensure that this illusion is preserved.
Ogawa Uzaemon, the Japanese translator, becomes a figure of more importance in this section. It comes to light that he intended to marry Orito, and she him, but their circumstances prevented it. He still loves her, however, and, being a trained samurai, he mounts a rescue mission with his trainer and mentor, Shuzai. When they arrive at the Shrine, however, Shuzai betrays Uzaemon to Enomoto, who kills him.
Orito, meanwhile, is doing everything in her power to escape the prison-like nunnery. Unlike the others, however, she isn't intended to be a mother, but a midwife to help the other women through their pregnancies. She develops friendships with the other women of the Shrine, who, like herself, are disfigured in some way, particularly Yayoi. Orito eventually discovers a way out and escapes the compound, but she acquires a guilty conscience for abandoning her friends to their misery, so she turns around and gives herself up to the Shrine of Enomoto.
The book then transitions to the third act, which deals mainly with the affairs of Nagasaki and Dejima on the whole. There enters an important third player in this national game: the English. Captain Penhaligon, suffering from a serious case of gout, leads the selfish English in their attempt to deceive and manipulate both the Dutch and the Japanese to kick the Dutch out of their position and take the trade route with Nagasaki for themselves. They do this with the help of Daniel Snitker, who assists them out of hatred for his former comrades, especially Vorstenbach (who has left for the Netherlands) and de Zoet. This conflict eventually escalates to actual war, as the English ship fires on Dejima, accidentally hitting Nagasaki as well. The English beat a retreat, and the situation is resolved for the moment. On the personal side, Jacob gives Magistrate Shiroyama the scroll listing the atrocities of Enomoto at the Shrine of Mount Shiranui. Shiroyama heroically sacrifices himself to kill Enomoto, poisoning the drink they both consume at their traditional game of Go, thus ending the cruel cycle of exploitation and freeing the women of the Shrine.
The book's epilogue chronicles the remaining days of Jacob de Zoet, who remains in Dejima for a long time, marries a Japanese woman (not Orito), has children, grows old, and eventually returns to the Netherlands, where he marries again and has a Dutch son. In his final moments of life, Jacob de Zoet thinks of Orito.
