The scene is the end of the Gilded Age in New York City. Ellen Thatcher is a young girl who aspires to be an actress. Young Jimmy Herf returns after years abroad, and rejects business school, becoming a reporter. George Baldwin is a lawyer who wins a big case, but continues to struggle to grow his business, eventually entering politics. The novel weaves the lives of these characters together throughout the narrative.

Manhattan Transfer also has a good number minor characters, some of whom only appear briefly, while others connect to the several plot lines. They range from a lowly street beggar to an aspiring architect, chasing after love and excitement in the fast pace of New York City, often encountering both frustration and defeat.

The story then jumps forward through World War I and into the Jazz Age, moving from one scene to the next in a fragmentary style. Many have compared this to a movie with many jumbled parts put together, portraying an overall impression of the metropolis through these glimpses. Contemporaries praised John Dos Passos for his ability to capture the soul of Manhattan, and Manhattan Transfer was quickly lauded as an important work.