In 1349, the community within the priory was severely affected by the outbreak of bubonic plague known as the Black Death. Eight members of the community died in three months during this pandemic. After the plague years, very few structural changes were carried out at the priory up until the end of 15th century. In 1558, Ireland was under the rule of Elizabeth I of England, a Protestant queen, and the property of the priory was confiscated by the crown. Elizabeth died in 1603, but the new King, James I, was no kinder to the priory: it became a courthouse, and the Dominicans were forced to leave and find places to stay in other houses.
From 1642 to 1649, Black Abbey played a major part in attempting to save both the Irish religion and the king, Charles I of England and of Ireland; the abbey hosted the government known as the Irish Catholic Confederation. These glory hours did not last long however. In March 1650, the English army under the command of Oliver Cromwell surrounded Kilkenny in a siege. Many people died from epidemic and hunger, many more fled before the city finally surrendered.
On Trinity Sunday, 22 May 1864, Black Abbey was reconsecrated by the bishop, and was finally opened again as a house of prayer.