Thomas Wolfe's You Can't Go Home Again follows the story of George Webber, a writer who has written a book based on his real-life experiences. However, when he returns to his hometown of Libya Hill, he faces the consequences of the candor in his book, which is so strong that the book is treated like a sort of exposé.

Book 1 begins with George having to return to his hometown in order to attend the funeral of his aunt. Libya Hill is caricatured as a typical deep south community that harbors a general small-town mentality, so much so that George's return is treated as a novel phenomenon and reported in the local newspaper. However, George feels the winds of change on the horizon because of talk of real estate development in the town.

In Book 2, he attends a party at the house of his wealthy lover, Esther, who is ten years his senior. While there, George observes the habits of the rich with hostility. No longer able to stand her lifestyle, George breaks things off with her. The onset of the Great Depression is hinted at.

Book 3 sees the Crash of 1929 and the publication of George's book. It causes quite a stir in his community, with several lambasting him for painting them in a negative light, and others offering him more salacious material to write about should he be interested. The book gets a better reception in New York, earning him fame for a while, until he falls out with his rich friends.

Book 4 finds him in Brooklyn and is just a collection of his observations of the life and people there, with special attention given to his editor, Foxhall "Fox" Edwards.

In Book 5, George moves to England. A new character is introduced: his landlady, Mrs. Purvis. He also meets an American writer, McHarg, and through this encounter becomes disillusioned with the idea of fame and fortune.

In Book 6, George travels to Germany, and commentary is made on the evils of the Nazi regime. George notes that its influence is reaching even America. He makes the comparison of Nazi Germany to his own hometown and concludes that "you can't go home again".

Book 7, the conclusion, is a letter written by George to Fox, detailing his life from childhood up until the present and acknowledging his regrets and mistakes.

From among the several million recorded words that Wolfe wrote during his career, the phrase that concludes one work and was chosen as the title for this novel has been probably the best-known of all the expressions he ever used. The adage “you can’t go home again” evidently was suggested first by Ella Winter, the widow of the writer Lincoln Steffens. This phrase seems apt, not on the most obvious literal level but rather in the sense that, in the flux of time and life, old ties and associations cannot remain the same, unchanged. Once they have been outgrown or cast off, old ways must be set aside as part of a past which cannot easily again be recaptured.

Wolfe’s last novel opens with George Webber’s return to New York, where Esther Jack receives him. He is apprised that his manuscript has been favorably reviewed by a well-known publishing house, which has sent an advance check for five hundred dollars. He also learns that his aged maiden aunt has died, and he travels southward, to return home for the first time in many years. On the way he meets Nebraska Crane, a friend and companion from his boyhood days who, though he has made a name for himself as a professional baseball player, feels that the best period of his career is behind him.

When George arrives in Libya Hill, he is treated by some as a visiting local celebrity. In newspapers, he is quoted with some inventiveness as expressing the fondest sentiments possible about his native city. Libya Hill has been overtaken by frenetic speculation in real estate and, in fact, in all realms of business, which temporarily has transformed it into a boom town. There is a pervasive atmosphere of change, both superficial and permanent. George, who feels oddly isolated even on native ground, comes to sense that his visit has been an act of farewell more than a homecoming.

Somewhat later, after his novel has been published, George ruefully, but with some amusement, notes the reaction it has stirred up among local people. Because much of his book was essentially based upon real characters, he has received letters complaining with some vehemence of the shame and disgrace he has brought upon those who once were his neighbors and friends. One anonymous writer threatens to kill him. On the other hand, someone else has offered to provide him with even more salacious material should he care to inquire.

By this time, George’s affair with Esther has run its course; after some oddly harrowing scenes at one of her social gatherings, he decides that he can turn away decisively from what he regards as her artificially cultivated, high-society circles and way of life. He turns instead to other women for short periods of time but finds none of them particularly endearing or even compatible. All the while, he has also become aware of changing fortunes all around him, brought about by the onset of the Great Depression. He learns that in Libya Hill land values have collapsed suddenly, with resulting hardships and uncertainty. In much of New York, signs of destitution and desperation can be seen at first hand; some moving passages describe dejected homeless men and the discovery of a suicide victim in the street. In spite of the many signs of desolation around George, and despite recurrent brooding loneliness, Wolfe’s hero is moved to reaffirm his faith in life and creation.

In describing the only enduring friendship from this period of his hero’s life, Wolfe paid unusual tribute to his editor Maxwell Perkins, whom he recast here as Foxhall Edwards. George Webber, who much earlier had lost his own father, is described as benefiting from a sort of spiritual adoption that provides him with needed guidance. To be sure, the editor depicted here seems in some ways foppish and has some strangely idiosyncratic habits. He also has a knack for getting around problems that seems at once cunning and guileless, but he is portrayed as fundamentally tolerant and fair-minded in ways that others of his profession are not.

Another fictional portrait from life of a well-known literary figure appears in the course of George’s further travels. During a visit to London he has the opportunity to meet the writer Lloyd McHarg, who was modeled upon Sinclair Lewis. When a newspaper story reports that McHarg has warmly praised George’s work, the young author manages to arrange a meeting with the great man. Although McHarg receives George on friendly, even cordial, terms, the younger man is struck not merely by his unprepossessing, in some ways ugly, appearance: In McHarg, he also believes that he can detect the trials and disappointments of fame and recognition. The widespread acclaim that McHarg had earned seems only to demonstrate that writers could not be satisfied merely with public acceptance. McHarg, in the sheer surfeit of his triumphs, has taken to constant traveling and drinking to allay the numbing boredom and loneliness that have befallen him.

Earlier in his career, Wolfe had shown some fondness for Germany, where he had traveled and where his first book, in translation, had been favorably received. Later, however, much had changed, and a sizable portion from the last part of this novel has to do with some striking and rather horrifying impressions that were gathered during travels under the Nazi regime. Although George Webber, as was Wolfe himself, is treated as an eminent foreign writer, he feels a pronounced uneasiness which sets in almost as soon as he arrives in Berlin. The Olympic Games held in the German capital are flanked by regimented demonstrations of marching men which hint strongly of preparations for war. People George meets are curiously reticent on political matters, though dark and unseemly rumors surface from time to time. The atmosphere of fear and compulsion seems more ubiquitous and more oppressive than any of the killings, gangster plots, or other manifestations of hatred and violence that America had ever known.

During a train trip to the west, George and some other travelers meet a curiously nervous little man, who is afraid he will be detained for currency violations. He presses upon George and the others some coins he had hidden away. When they change trains at the frontier, they discover that the man, who is Jewish, is attempting to escape while smuggling much of his money out of the country. In a brutal, wrenching confrontation with Nazi police, he is apprehended. The others must, helplessly, leave him to his fate. The novel concludes with George’s return to New York, where he writes a long letter to Foxhall Edwards, summarizing his beliefs and setting forth his artistic credo. Though he will work no longer under his former editor and friend, he believes that some explanation—and some exposition of the directions his life has taken—is required. At the end, George maintains that the forces of time and change cannot be resisted and that the past he had known must be put behind him.