Holmes read law at Harvard University before deciding on a medical career; and, following studies at Harvard and in Paris, he received his degree from Harvard in 1836. He practiced medicine for 10 years, taught anatomy for two years at Dartmouth College (Hanover, N.H.), and in 1847 became professor of anatomy and physiology at Harvard. He was later made dean of the Harvard Medical School, a post he held until 1882. His most important medical contribution was that of calling attention to the contagiousness of puerperal fever (1843).

Holmes achieved his greatest fame, however, as a humorist and poet. He wrote much poetry and comic verse during his early school years; he won national acclaim with the publication of “ Old Ironsides” (1830), which aroused public sentiment against destruction of the USS Constitution, an American fighting ship from the War of 1812. Beginning in 1857, he contributed his “Breakfast-Table” papers to The Atlantic Monthly and subsequently published The Autocrat of the Breakfast-Table (1858), The Professor of the Breakfast-Table (1860), The Poet of the Breakfast-Table (1872), and Over the Teacups (1891), written in conversational style and displaying Holmes's learning and wit.

Among his other works are the poems “The Chambered Nautilus” (1858) and “The Deacon's Masterpiece, or ‘The Wonderful One-Hoss Shay' ” (1858), often seen as an attack on Calvinism, and the psychological novel Elsie Venner (1861), also an attack on Calvinism that aroused controversy.