The son of George Combe (1745-1816), a brewer, he was a younger brother of George Combe. After attending the Royal High School, he became a surgeon's pupil in 1812, obtaining his diploma in 1817, when he went to Paris to complete his medical studies, specialising in anatomy and investigating cerebral morphology under Spurzheim's supervision. He returned to Edinburgh in 1819, intending to start a practice there. However, illness compelled him to spend the next two winters in the south of France and Italy. In 1823, he began to practise in Edinburgh. Combe joined his brother and others in establishing the Phrenological Journal, following a debate at the Royal Medical Society in which he felt he had scored a major victory over the opponents of phrenology, but of which the Society declined to publish any account. In 1825, he graduated M.D. at Edinburgh. His practice grew quickly because of his ability to listen, and his exceptional professional courtesy. In 1827, he was elected President of the Edinburgh Phrenological Society. In 1831, he published with great success his Observations on Mental Derangement. Ill health enforced regular visits abroad. In 1834 he published his bestselling Physiology applied to Health and Education. Early in 1836 he received the appointment of physician to King Léopold I of Belgium and moved to Brussels; but his health again failed, and he returned to Edinburgh in the same year. He soon completed and published his Physiology of Digestion (1836), which reached a ninth edition in 1849. A very considerable practice now absorbed all his energies, and in 1838 he was appointed a physician to Queen Victoria. In 1840, he published his last, and he considered his best book, The Physiological and Moral Management of Infancy. The sixth edition appeared in 1847. During his later years, tuberculosis made serious advances. Two winters in Madeira and a voyage to the United States failed to improve things, and he died while on a visit to a nephew at Gorgie Mills, on the south-west side of Edinburgh, on 9 August 1847. Combe never married. He is buried with his grandfather, George Combe, brewer, in St Cuthbert’s Churchyard.