He was born at Fawsley, Northamptonshire, and educated at Magdalen College, Oxford (then Magdalen Hall). He was ordained and became vicar of his home town of Fawsley in 1637, but soon resigned and became chaplain successively to Lord Saye and Sele, Lord Berkeley, and Prince Charles Louis, nephew of King Charles I and afterwards elector palatine of the Rhine.
In 1641, Wilkins published an anonymous treatise entitled Mercury, or The Secret and Swift Messenger. It was a small but comprehensive work on cryptography, and a timely gift to the diplomats and leaders of the imminent English Civil War. In 1648 he became warden of Wadham College, Oxford. Under him the college was extraordinarily prosperous, for, although a supporter of Oliver Cromwell, he was in touch with the most cultured Royalists, who placed their sons in his charge. In 1659, Richard Cromwell appointed him master of Trinity College, Cambridge.
At the Restoration in 1660 he was deprived of the position given him by Cromwell, but was appointed prebendary of York and rector of Cranford, Middlesex. In 1661 he was preacher at Gray's Inn, and in 1662 vicar of St Lawrence Jewry, London. He became vicar of Polebrook, Northamptonshire, in 1666, prebendary of Exeter in 1667, and in the following year prebendary of St Paul's and bishop of Chester.
Possessing strong scientific tastes, Wilkins was the chief founder of the Royal Society and its first secretary. He died in London. His numerous written works include An Essay towards a Real Character and a Philosophical Language (London, 1668), in which he proposes a new universal language for the use of philosophers. He is remembered also for a curious work entitled The Discovery of a World in the Moon (1638, 3rd ed., with an appendix "The possibility of a passage thither," 1640). Other works are A Discourse Concerning a New Planet (1640); Mercury, or the Secret and Swift Messenger (1641), a work of some ingenuity on the means of rapid correspondence; and Mathematical Magick (1648).