The Autocrat of the Breakfast-Table named the Atlantic Monthly magazine, to which he regularly contributed articles of light humor. His first published poem, “Old Ironsides,” successfully protested the proposed scrapping of the warship Constitution. His poem “The Deacon’s Masterpiece” is a rollicking Unitarian critique of Calvinistic religion.

Dr. Holmes was a dominant member of the Saturday Club whose notables included Ralph Waldo Emerson—whose biography Holmes wrote. Other works by him are Homeopathy and Its Kindred Delusions and a paper on "The Contagiousness of Puerperal Fever" detailing his major medical discovery.

Holmes was dean of the Harvard Medical School as well as a longtime professor of anatomy. His father, who wrote the first history of the town of Cambridge, was beloved pastor of the First Parish and First Church of Cambridge until the Unitarian controversy arose. His son, Oliver Wendell Holmes, Jr., was a distinguished member of the Supreme Court of the United States.