The book begins with the death of Helen Carey, the beloved mother of nine-year-old Philip Carey. Philip has a club foot and his father had died a few months earlier. Now orphaned, he is sent to live with his aunt and uncle, Louisa and William Carey in Blackstable, a town in Kent.
Philip lives at his uncle's vicarage. Aunt Louisa tries to be a mother to Philip, but his uncle is cold towards him. Philip's uncle has a vast collection of books, and Philip enjoys reading to escape his mundane existence. After less than a year, Philip is sent to a boarding school. His uncle and aunt plan for him to attend Oxford. Philip's disability and sensitive nature make it difficult for him to befriend other pupils. Philip learns that he could earn a scholarship for Oxford, which both his uncle and school headmaster view as wise, but Philip insists on going to Germany.
In Heidelberg, Philip lives at a boarding house with other foreigners and enjoys Germany. Philip's guardians persuade him to move to London for an apprenticeship. His colleagues there resent him, believing he is a "gentleman". He goes on a business trip with one of his managers to Paris and is inspired to study art in France.
In Paris, Philip attends art classes and makes new friends, including Fanny Price, a poor and determined but talentless art student and a loner. Fanny Price falls in love with Philip, but he does not know and has no such feelings for her. She subsequently commits suicide.
Bette Davis (as Mildred) and Leslie Howard in the 1934 film versionPhilip realizes that he will never be a professional artist. He returns to his uncle's house in England to study medicine, his late father's field. He struggles at medical school and meets Mildred, who works as a waitress in a tea shop. He falls desperately in love with her, and they date regularly, although she does not show him affection. Mildred tells Philip she will marry another man, leaving him heartbroken; Philip subsequently enters into an affair with Norah Nesbit, a kind and sensitive author of penny romance novels. Later Mildred returns, pregnant, and confesses that the man for whom she had abandoned Philip never married her, as he was already married with three children.
Philip breaks off his relationship with Norah and supports Mildred financially, which he can ill afford. To Philip's dismay, after Mildred has her baby, she falls in love with Philip's good friend Harry Griffiths and runs away with him. About a year later, Philip runs into Mildred and, feeling sympathy, takes her in again. Though he no longer loves her, he becomes attached to her baby. When he rejects her advances she becomes angry, destroys most of his belongings, and leaves forever. In shame, and quickly running out of money, Philip leaves the house for good. He meets Mildred once more, towards the end of the novel, when she summons him for his medical opinion. She is suffering symptoms of syphilis from her work as a prostitute. Philip advises Mildred to give up that life but she declines and exits the plot with her fate unknown.
While working at a hospital, Philip befriends a family man, Thorpe Athelny, who has lived in Toledo, Spain, and is enthusiastically translating the works of St. John of the Cross. Philip invests in mines but is left nearly penniless because of events surrounding the Boer War. Unable to pay his rent, he wanders the streets for several days before the Athelnys take him in and find him a department store job, which he hates. His talent for drawing is discovered and he receives a promotion and a raise in salary, but his time at the store is short-lived.
After his uncle William dies, Philip inherits enough money to allow him to finish his medical studies and he finally becomes a licensed physician. Philip is temporarily placed as locum with Dr. South, a general practitioner in Dorsetshire. Dr. South is an old, cantankerous physician whose wife is dead and whose daughter is estranged. However, Dr. South takes a shine to Philip's humour and personable nature, eventually offering Philip a partnership in his medical practice. Although flattered, Philip refuses because he plans to visit Spain.
He goes on a small summer holiday with the Athelnys, hop-picking in the Kent countryside. There he finds that one of Athelny's daughters, Sally, likes him. In a moment of romantic abandon one evening they have sex, and when she thinks she is pregnant, Philip decides to marry Sally and accept Dr. South's offer, instead of travelling the world as he had planned. They meet in the National Gallery where, though learning that it was a false alarm, Philip becomes engaged to Sally, concluding that "the simplest pattern – that in which a man was born, worked, married, had children, and died – was likewise the most perfect". He stops the pursuit of happiness and decides to be content with his lot.
