The Makioka Sisters is the story of four sisters in a wealthy Japanese merchant family that is in declining fortune in the years leading up to World War II. The novel focuses on the viewpoint of Sachiko, the second oldest sister, who with her husband Teinosuke play an increasingly important role in the family's affairs as the oldest sister Tsuruko and her husband, Tatsuo the head of the "main house" of the family, move away from the family's seat in Osaka to Tokyo. Meanwhile, Japan becomes increasingly hostile toward China as it prepares for war. The Makioka family sees many of its European acquaintances in Japan leaving for home as the situation in Europe moves toward war.

The family's affairs are primarily concerned with the two younger sisters, Yukiko and Taeko, who live most of the time with Sachiko. Yukiko, a shy and quiet woman, is well past the age at which women of her class should be married, but no suitable husband has been found for her. Each prospective suitor has been either ruled out by the main house for something in his background or else refused by Yukiko herself. Taeko, the youngest sister, cannot marry before Yukiko. As a young woman, Taeko had eloped with her lover Okubata causing a minor scandal before she returned home and actually got married.

The family struggles with maintaining proper outward appearances while dealing with the seemingly docile but stubborn Yukiko and the increasingly independent Taeko, who begins to see other men while she waits for a husband to be found for Yukiko. Despite several attempts to match Yukiko with a husband, something always seems to break down the negotiations. When Yukiko herself sours an ongoing negotiation by refusing to met with a suitor, Sachiko grows to resent her for her apparent ingratitude. Taeko disturbs the main house of the family by announcing her intention to learn sewing and make clothing for a living. The main house insists that she either come live with them in Tokyo and wait to be married or be disinherited. Taeko leaves Sachiko's house to live on her own.

A match is finally made for Yukiko with a man named Mimaki, a son from a noble Tokyo family. During the negotiations, which are handled mainly by Teinosuke, Sachiko learns that Taeko is pregnant and the father is a bartender named Miyoshi. Ever concerned with ruining Yukiko's chances of marriage, the family hides Taeko away during her pregnancy. Tragically, her child dies shortly after birth. Nevertheless, Taeko is married to Miyoshi and the novel closes as Yukiko sets off to Tokyo to be married.