Educated at Merton College, Oxford and taking his MA degree in 1530, he became Registrar of the University of Oxford in 1532 then (by royal appointment) its first Regius Professor of divinity in 1536. Taking his doctorate in divinity on 10 July 1536, he was subsequently made master of Whittington College, London, rector of St Dunstan-in-the-East and then Cuxham, Oxfordshire, principal of St. Alban's Hall, and divinity reader at Magdalen College.

Some (possibly unreliable) accounts have him renouncing Catholicism and the authority of the Pope at Oxford and (on 15 May 1547) at St Paul's Cross on the accession of the Protestant Edward VI. However, even if the accounts are reliable, he soon afterwards he became a Catholic again and was thus replaced in his professorship with Peter Martyr. He and Martyr held a public disputation in 1549, and soon afterwards Smith was arrested, but only imprisoned for a short while.

On release he left to become professor of divinity at Louvain, returning on the accession of Mary to become canon of Christ Church and royal chaplain and take a major part in proceedings against Thomas Cranmer, Nicholas Ridley, and Hugh Latimer. Regaining most of his benefices, he lost them all again when Elizabeth succeeded Mary, and was briefly imprisoned in the house of Archbishop Matthew Parker. On release, he again fled to the continent, this time to Douai, where Mary's widower Philip II of Spain appointed him dean of St. Peter's church and then (on Philip II's inauguration of University of Douai on 5 October 1562) the university's chancellor and professor of theology.