The broad and deep collections of American literature at the Lilly Library are one of its principal strengths. 

From early works such as Anne Bradstreet's 1650 The Tenth Muse Lately Sprung Up in America to 18th century prose and verse, from 19th and 20th century groundbreaking authors to science fiction and detective novels, the holdings span the evolution of American literature. 

Of particular note are collections of of James Fenimore Cooper, Edgar Allan Poe, Henry Wadsworth Longfellow, Nathaniel Hawthorne, Ralph Waldo Emerson, Henry David Thoreau, Herman Melville, Mark Twain, and Walt Whitman.

Holdings in twentieth-century American literature are extensive, including the principal archives of Upton Sinclair, Max Eastman, Sylvia Plath, and Galway Kinnell, as well as notable collections from Edith Wharton, Ezra Pound, William Carlos Williams, F. Scott Fitzgerald, Ernest Hemingway, and John Dos Passos.