In 1521 he was asked to study the problem of Henry VIIIs marriage. He incurred Henrys anger by defending the validity of the kings marriage with Catherine and later by rejecting Henrys claim to be the supreme head of the Church of England.
In an attempt to be rid of him, Henry first had him accused of not reporting all the revelations of the nun of Kent, Elizabeth Barton. John was summoned, in feeble health, to take the oath to the new Act of Succession. He and Thomas More refused because the Act presumed the legality of Henrys divorce and his claim to be head of the English Church. They were sent to the Tower of London, where Fisher remained 14 months without trial. They were finally sentenced to life imprisonment and loss of goods.
When the two were called to further interrogations, they remained silent. Fisher was tricked, on the supposition he was speaking privately as a priest, and declared again that the king was not supreme head. The king, further angered that the pope had made John Fisher a cardinal, had him brought to trial on the charge of high treason. He was condemned and executed, his body left to lie all day on the scaffold and his head hung on London Bridge. More was executed two weeks later.