The firm initially specialized in legal treatises and imported titles. Even so, in the early years Little and Brown published William H. Prescott's Ferdinand and Isabella, Jones Very's first book of poetry (edited by Ralph Waldo Emerson), Letters of John Adams and works by James Russell Lowell and Francis Parkman. The firm was the original publisher of United States Statutes at Large beginning in 1845, under authority granted by a joint resolution of Congress. (In 1874, Congress transferred the authority to publish the Statutes at Large to the Government Printing Office, which has been responsible for producing the set since that time.) In 1853 Little, Brown began publishing the works of British poets from Chaucer to Wordsworth. There were ninety-six volumes published in the series in five years.
In 1859 John Bartlett became a partner in the firm. He held the rights to his Familiar Quotations, and Little, Brown published the 15th edition of the work in 1980, 125 years after its first publication.
John Murray Brown, James Brown's son, took over when Augustus Flagg retired in 1884. In the 1890s Little, Brown expanded into general publishing, including fiction. In 1896 it published Quo Vadis. In 1898 Little, Brown purchased a list of titles from the Roberts Brothers firm.
Other prominent authors published by Little, Brown in the 20th and early 21st centuries have included Donald Barthelme, Catherine Drinker Bowen, Hortense Calisher, Bruce Catton, A. J. Cronin, Peter De Vries, J. Frank Dobie, Sarah Dunant, John Feinstein, C. S. Forester, John Fowles, Malcolm Gladwell, Pete Hamill, Lillian Hellman, Oliver Wendell Holmes, Sr., Henry Kissinger, Elizabeth Kostova, Norman Mailer, William Manchester, Nelson Mandela, John P. Marquand, Masters and Johnson, Stephenie Meyer, Rick Moody, Ogden Nash, Edwin O'Connor, Erich Maria Remarque, J. D. Salinger, Alice Sebold, David Sedaris, George Stephanopoulos, Gore Vidal, Bob Vila, David Foster Wallace, Evelyn Waugh, P. G. Wodehouse, and Herman Wouk. Little, Brown also published the photography of Ansel Adams.
In May 2006, the publishing company received some brief bad publicity over plagiarism allegations levied against Kaavya Viswanathan for her book How Opal Mehta Got Kissed, Got Wild, and Got a Life.
Little, Brown and Company also published Stephenie Meyer's Twilight series, "Twilight, New Moon, Eclipse and Breaking Dawn." They also released Breaking Dawn which is already out in stores