His most highly regarded and influential works were published in the 1960s, and include The Sot-Weed Factor, a whimsical retelling of Maryland's colonial history; Giles Goat-Boy, a satirical fantasy in which a university is a microcosm of the Cold War world; and Lost in the Funhouse, a self-referential and experimental collection of short stories.

[2] Barth's career began with The Floating Opera and The End of the Road, two short realist[14] novels that deal with controversial topics: suicide and abortion, respectively.

[15][16] The Sot-Weed Factor (1960; the title is an archaic phrase meaning "the tobacco merchant") was initially intended as completing a trilogy of "realist" novels, but developed into a different project[14] and is seen as marking Barth's discovery of postmodernism.

[17] It reimagines the life of Ebenezer Cooke, a poet in colonial Maryland, and recounts a series of fantastic and often comic adventures, including an account of the story of Captain John Smith and Pocahontas.

[19] George Giles, a boy raised as a goat, discovers his humanity and sets out on a quest to become a "Grand Tutor", a messiah-like spiritual leader within the university.

Later novels such as The Tidewater Tales (1987) and The Last Voyage of Somebody the Sailor (1991) continue in the metafictional vein, using writers as protagonists who interact with their own and other stories in elaborate ways.

He said, "I don't know what my view of history is, but insofar as it involves some allowance for repetition and recurrence, reorchestration, and reprise [...] I would always want it to be more in the form of a thing circling out and out and becoming more inclusive each time.

[32] The essay was widely considered a statement of "the death of the novel",[33][34] but Barth later insisted that he had merely been making clear that a particular stage in history was passing, and pointing to possible directions from there.