Persons came from a less than distinguished background, yet he was, through the favour of the local parson, enrolled at St Mary's Hall at Oxford in 1562. After completing his studies with distinction, he became a tutor at Balliol College in 1568, but in February 1574 he resigned partly because of his strong Catholic leanings and partly because of quarrels he had with the establishment. He went abroad, travelled to Rome, and within the year was reconciled and became a Jesuit, being ordained at Rome on 3 July, 1575.

Over the next few years, Persons pushed the case of the "English Mission" and was instrumental in its eventual acceptance and approval by Dr. William Allen.

In 1580 he accompanied Edmund Campion on the English Mission, and was extremely successful in reconciling Catholics and spreading his books and pamphlets. He wrote several tracts, and was instrumental in allowing the Jesuits to gain ground in England. Much of the efforts he made laid the groundwork for the Jesuits who came after him, including establishing Catholic refuges and developing the intricate network of Catholic families around England, prepared to harbour priests.

Campion was arrested in July 1581, and the press Persons was using to print his material was discovered the following months, Persons fled to France. He was recalled to Rome and then sent to Spain in 1588 where he founded the colleges of Valladolid, Seville, and Madrid (1589, 1592, 1598). In 1594 he also greatly expanded on the school of St Omers in Artois, for Catholic boys, which today is continued through lineal descent at the college of Stonyhurst in Lancashire.

Amidst conflict in Rome during the late 1590's, Persons was again recalled, and although he was never made a cardinal he assisted in helping to reorganise the heirarchy which at times saw him in opposition to many of the senior clergy. He remained in charge of the English Colleges, yet almost lost his post in 1604 when the pope, Clement VIII was advised by the French Ambassador that James I would look favourably upon the church if it could be seen as independant from the Jesuits. Accordingly Clement VIII had Persons effectively exiled, but this decision was reversed by Paul V who succeeded him in 1605.

Persons returned to his post at the English Colleges, and although it was an unpopular decision, remained there until his death in 1610.