He was the son of John Jewel of Buden, Devon, was educated under his uncle John Bellamy, rector of Hampton, and other private tutors until his matriculation at Merton College, Oxford, in July 1535.

There he was taught by John Parkhurst, afterwards bishop of Norwich; but on August 19, 1539 he was elected scholar of Corpus Christi College, Oxford. He graduated BA in 1540, and MA in 1545, having been elected fellow of his college in 1542. He made some mark as a teacher at Oxford, and became after 1547 one of the chief disciples of Pietro Martire Vermigli, known in England as Peter Martyr. He graduated BD in 1552, and was made vicar of Sunningwell, and public orator of the university, in which capacity he had to compose a congratulatory epistle to Mary on her accession. In April 1554 he acted as notary to Cranmer and Ridley at their disputation, but in the autumn he signed a series of Catholic articles. He was, nevertheless, suspected, fled to London, and thence to Frankfort, which he reached in March 1555. There he sided with Coxe against Knox, but soon joined Martyr at Strasbourg, accompanied him to Zürich, and then paid a visit to Padua.

Under Elizabeth's succession he returned to England, and made earnest efforts to secure what would now be called a low-church settlement of religion; he was strongly committed to the Elizabethan reforms. Indeed, his attitude was hardly distinguishable from that of the Elizabethan Puritans, but he gradually modified it under the stress of office and responsibility. He was one of the disputants selected to confute the Romanists at the conference of Westminster after Easter 1559; he was select preacher at St Paul's Cross on June 15; and in the autumn was engaged as one of the royal visitors of the western counties. His congé d'élire as bishop of Salisbury had been made out on July 27, but he was not consecrated until January 21, 1560.

He now constituted himself the literary apologist of the Elizabethan Settlement. He had on November 26, 1559, in a sermon at St Paul's Cross, challenged all comers to prove the Roman Catholic case out of the Scriptures, or the councils or Fathers for the first six hundred years after Christ. He repeated his challenge in 1560, and Dr Henry Cole took it up. The chief result was Jewel's Apologia ecclesiae Anglicanae, published in 1562, which in Bishop Creighton's words is the first methodical statement of the position of the Church of England against the Church of Rome, and forms the groundwork of all subsequent controversy. The work was translated into English by Anne Bacon to reach a wider audience and was a significant step in the intellectual justification of Protestantism in England.

A more formidable antagonist than Cole now entered the lists in the person of Thomas Harding, an Oxford contemporary whom Jewel had deprived of his prebend in Salisbury Cathedral for recusancy. He published an elaborate and bitter Answer in 1564, to which Jewel issued a Reply in 1565. Harding followed with a Confutation, and Jewel with a Defence of the Apology in 1566 and 1567; the combatants ranged over the whole field of the Anglo-Roman controversy, and Jewel's theology was officially enjoined upon the Church by Archbishop Bancroft in the reign of James I. Latterly Jewel had been confronted with criticism from a different quarter. The arguments that had weaned him from his Zwinglian simplicity did not satisfy his unpromoted brethren, and Jewel had to refuse admission to a benefice to his friend Lawrence Humphrey, who would not wear a surplice.

He was consulted a good deal by the government on such questions as England's attitude towards the Council of Trent, and political considerations made him more and more hostile to Puritan demands with which he had previously sympathized. He wrote an attack on Thomas Cartwright; which was published after his death by Whitgift. Collapsing after a sermon at Lacock, Wiltshire, he was taken to the episcopal manor house of Monkton Farleigh where he died on September 23, 1571. He was buried in Salisbury Cathedral, where he had built a library. Richard Hooker, who speaks of Jewel as the "worthiest divine that Christendom bath bred for some hundreds of years," was one of the boys whom Jewel prepared in his house for the university; and his Ecclesiastical Polity owes much to Jewel's training.

Jewel's works were published in a folio in 1609 under the direction of Bancroft, who ordered the Apology to be placed in churches, in some of which it may still be seen chained to the lectern; other editions appeared at Oxford (1848, 8 vols) and Cambridge (Parker Soc., 4 vols). See also Gough's Index to Parker Soc. Publ.; John Strype's Works (General Index); Calendars of Domestic and Spanish State Papers; Dixon's and Frere's Church Histories; and Dictionary of National Biography (art. by Bishop Creighton).

A house at Bishop Wordsworth's School in Salisbury is named for him.