The book tells the story of a Malayali family living in southwest India, in the Kerala state, with the narrative spanning three generations, from 1900 to 1977.

The novel revolves around three generations of an Orthodox Saint Thomas Christian[2] family living in the town of Parambil, in the southwest Indian state of Kerala.

The story begins in 1900 with a 12-year-old girl named Mariamma who moves there to marry a 40-year-old widower, called Big Appachen, in an arranged marriage.

Mariamma soon learns of a problem in the family, which they call "the Condition:" in every generation, one or more individuals dies from drowning under suspicious circumstances.

Meanwhile, Digby Kilgore, a physician who was unable to get the training he needed in Scotland because of his Catholic religion, joins the Indian Medical Service in Madras.

Dr. Orqvist tries to repair Digby's hands, and enlists Elsie, the young daughter of a friend, to help with his rehabilitation by teaching him to draw.

When Elsie disappears and is believed dead, Big Ammachi helps Philipose rear Mariamma, thinking her to be her son's daughter.

The novel was inspired by the life story of Verghese's mother Mariamma, to whom the book is dedicated, and is set in southern India where the author's family came from.

[3] Solomon further criticized the characters' development stating the novel "focuses almost entirely on good people (to whom many terrible things happen), and given the complexity of human beings, the surfeit of grace sometimes feels unrealistic and even pretentious...".