Having given up on the study of law, Holmes switched to medicine. After leaving his childhood home in Cambridge during the autumn of 1830, he moved into a boardinghouse in Boston to attend the city's medical college. At that time, students studied only five subjects: medicine, anatomy and surgery, obstetrics, chemistry and materia medica. Holmes became a student of James Jackson, a physician and the father of a friend, and worked part-time as a chemist in the hospital dispensary. Dismayed by the "painful and repulsive aspects" of primitive medical treatment of the time—which included practices such as bloodletting and blistering—Holmes responded favorably to his mentor's teachings, which emphasized close observation of the patient and humane approaches.Despite his lack of free time, he was able to continue writing. He wrote two essays during this time which detailed life as seen from his boardinghouse's breakfast table. These essays, which would evolve into one of Holmes's most popular works, were published in November 1831 and February 1832 in the New England Magazine under the title "The Autocrat of the Breakfast-Table".In 1833, Holmes traveled to Paris to further his medical studies. Recent and radical reorganization of the city's hospital system had made medical training there highly advanced for the time. At twenty-three years old, Holmes was one of the first Americans trained in the new "clinical" method being advanced at the famed École de Médecine.Since the lectures were taught entirely in French, he engaged a private language tutor. Although far from home, he stayed connected to his family and friends through letters and visitors (such as Ralph Waldo Emerson). He quickly acclimated to his new surroundings. While writing to his father, he stated, "I love to talk French, to eat French, to drink French every now and then."At the hospital of La Pitié, he studied under internal pathologist Pierre Charles Alexandre Louis, who demonstrated the ineffectiveness of bloodletting, which had been a mainstay of medical practice since antiquity. Dr. Louis was one of the fathers of the méthode expectante, a therapeutic doctrine that states the physician's role is to do everything possible to aid nature in the process of disease recovery, and to do nothing to hinder this natural process.Upon his return to Boston, Holmes became one of the country's leading proponents of the méthode expectante. Holmes was awarded his M.D. from Harvard in 1836; he wrote his dissertation on acute pericarditis.His first collection of poetry was published later that year, but Holmes, ready to begin his medical career, wrote it off as a one-time event. In the book's introduction, he mused: "Already engaged in other duties, it has been with some effort that I have found time to adjust my own mantle; and I now willingly retire to more quiet labors, which, if less exciting, are more certain to be acknowledged as useful and received with gratitude".
His birthplace, a house just north of Harvard Yard, was said to have been the place where the Battle of Bunker Hill was planned.He was the first son of Abiel Holmes (1763–1837), minister of the First Congregational Church and avid historian, and Sarah Wendell, Abiel's second wife. Sarah was the daughter of a wealthy family, and Holmes was named for his maternal grandfather, a judge. The first Wendell, Evert Jansen, left Holland in 1640 and settled in Albany, New York. Also through his mother, Holmes was descended from Massachusetts Governor Simon Bradstreet and his wife, Anne Bradstreet (daughter of Thomas Dudley), the first published American poet.
From a young age, Holmes was small and suffered from asthma, but he was known for his precociousness. When he was eight, he took his five-year-old brother, John, to witness the last hanging in Cambridge's Gallows Lot and was subsequently scolded by his parents. He also enjoyed exploring his father's library, writing later in life that "it was very largely theological, so that I was walled in by solemn folios making the shelves bend under the load of sacred learning." After being exposed to poets such as John Dryden, Alexander Pope and Oliver Goldsmith, the young Holmes began to compose and recite his own verse. His first recorded poem, which was copied down by his father, was written when he was 13.