He became a fellow of Queens' College, Cambridge, in 1530, and in 1533 was appointed a public reader or professor. He lectured in the schools on natural philosophy, and on Greek in his own rooms. In 1540 Smith went abroad, and, after studying in France and Italy and taking a degree of law at Padua, returned to Cambridge in 1542.
He now took the lead in the reform of the pronunciation of Greek, his views after considerable controversy being universally adopted. He and his friend Sir John Cheke were the great classical scholars of the time in England. In January 1543/4 he was appointed first Regius Professor of Civil Law. He was vice-chancellor of the university the same year, and became chancellor to the bishop of Ely, by whom he was ordained priest in 1546. In 1547 he became provost of Eton and dean of Carlisle.
He early adopted Protestant views, a fact which brought him into prominence when Edward VI came to the throne. During Somerset's protectorate he entered public life and was made a secretary of state, being sent on an important diplomatic mission to Brussels. In 1548 he was knighted. On the accession of Mary he was deprived of all his offices, but in the succeeding reign was prominently employed in public affairs. He became a member of parliament, and was sent in 1562 as ambassador to France, where he remained till 1566; and in 1572 he again went to France in the same capacity for a short time. He remained one of Elizabeth's most trusted Protestant counsellors, being appointed in 1572 chancellor of the order of the Garter and a secretary of state.