The story takes place in ancient India, where Siddhartha decides to leave his home in the hope of gaining spiritual illumination by becoming an ascetic Śamaṇa.

Eventually the pair seek out and personally speak with the enlightened Gautama, but although Govinda hastily joins the Buddha's order, Siddhartha does not.

Thus Siddhartha becomes a rich man and Kamala's lover, but in his middle years he realizes that the luxurious lifestyle he has chosen is merely a game that lacks spiritual fulfillment.

Some years later, Kamala, now a Buddhist convert, is traveling to see the Buddha on his deathbed, accompanied by her reluctant young son, when she is bitten by a venomous snake near the river bank.

After Kamala's death, Siddhartha attempts to console and raise the furiously resistant boy, until one day the child flees altogether.

Listening to the river with Vasudeva, Siddhartha realizes that time is an illusion and that all of his feelings and experiences, even those of suffering, are part of a great and ultimately jubilant fellowship of all things connected in the cyclical unity of nature.

A major preoccupation of Hesse in writing Siddhartha was to cure his "sickness with life" (Lebenskrankheit) by immersing himself in Indian philosophy such as that expounded in the Upanishads and the Bhagavad Gita.

[4] Ralph Freedman mentions how Hesse commented in a letter "[my] Siddhartha does not, in the end, learn true wisdom from any teacher, but from a river that roars in a funny way and from a kindly old fool who always smiles and is secretly a saint.

[6] Freedman also points out how Siddhartha described Hesse's interior dialectic: "All of the contrasting poles of his life were sharply etched: the restless departures and the search for stillness at home; the diversity of experience and the harmony of a unifying spirit; the security of religious dogma and the anxiety of freedom.

[9] In the following year, the film version of the novel was released as Siddhartha, starring Shashi Kapoor and directed by Conrad Rooks.

Musical compositions based on the novel have included Claude Vivier's symphonic poem, Siddhartha (1976),[10][11] and Pete Townshend's song "The Ferryman", written for an amateur dramatisation in June 1976.