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.