The Catholics of Galway joined the general rebellion of the Catholic Confederacy in 1641. There was a further rebellion by the Catholic population of Ireland which included the Gaelic and the “Old English” or Norman people.

The deep and complicated structure of Ireland in 1641 was however not a matter on which the Puritan element in the House of Commons, including Cromwell, was inclined to ponder. A reaction of simple passionate horror to the rising - or rebellion as it was always called by the English at the time - was occasioned by the news that the revolt had also been accompanied by a general massacre of English men, women and children, turned out of their homes, some dying by the sword, some out of starvation and exposure as they tried to make their way half-naked towards the English-held enclaves such as Dublin. The legend of the Irish massacres was born.

In July of 1649, the Bubonic plague was introduced into the town of Galway from a Spanish ship. The population of the town had increased considerably at this time due to families from the country, flocking in for protection.

The plague continued until the end of April of the following year, eventually killing upwards of 3,700 of the inhabitants. This included 210 from the most respected families.

Those who survived had escaped the town until it was almost entirely deserted. They assembled in the country and made a collection to pay physicians to tend to the sick. They formed a committee of health, and finally succeeded in eradicating the infection.

The execution of Charles I in 1649, on the orders of Oliver Cromwell, brought the English Civil War to an end. England became a Commonwealth or republic ruled by parliament with Cromwell as Lord Protector.

Cromwell and his army of well trained and experienced soldiers, called Ironsides, came to Ireland in August 1649 with the intention of subduing the rebellion and stamping out all opposition to parliament. Cromwell, a Puritan, ‘believed he was an instrument of divine retribution for (alleged) atrocities committed by Catholics against Protestants in 1641 and he accordingly gave orders to deny mercy to Catholics.’ His campaign was savage and is remembered for the slaughter of women and children as well as unarmed captives. He captured Drogheda and slaughtered the garrison. At Wexford the townspeople as well as the garrison were put to death. Cork, Kinsale, Bandon, Youghal and Clonmel had surrendered before he returned to England in May 1650. His son-in-law, Henry Ireton, continued the campaign. He captured Waterford, then Athlone and Portumna and finally attacked Limerick which surrendered after a four-month siege. Ireton died in November 1651 and was replaced by General Ludlow. Ludlow proceeded to break down the resistance of the remaining garrisons.

Eventually a force arrived outside Galway led by the Cromwellian, Sir Charles Coote. Blockaded by land and from the sea, the situation in Galway grew desperate due to starvation. The political leader in the town was the King's Lord Deputy in Ireland: Ulick Burke, Marquis of Clanricarde, descendant of Richard de Burgo.

On May 12, 1652, Galway surrendered to Sir Charles Coote, Lord President of Connacht. Only eight of the townsmen gave their assent to the final articles of surrender. By contrast, 106 of the leading citizens of the town, including Nicholas Athy, refused to sign the final articles.

Henceforth the most violent acts of oppression and injustice openly took place without any control. The king's arms and every other emblem of royalty were torn down. The churches and abbies were converted into stables for the dragoons, the chalices and sacred vessels used as drinking cups, and the old and valuable libraries of the clergy burnt or sold to the shops. The mayor and aldermen, though expressly protected by the articles, were repeatedly abused and dragged to prison, for daring to argue with soldiers, who set no bounds to their brutality and violence.

Government agents were employed to round up beggars, widows and orphans to be transported to the sugar plantations of the West Indies where they became servants and indentured slaves. The Puritan Parliamentarians persecuted not only Catholics but Ulster Presbyterians, members of the Church of Ireland and those of other minority religions. Priests were hanged, exiled or transported to the West Indies and Puritan preachers were brought over from England to replace them.

On the 30th of October, 1655, they ordered, "that all the Irish and other popish inhabitants should be forthwith removed out of the town, in order that accommodation should be provided for such English Protestants, whose integrity to the State would entitle them to be trusted in a place of such importance."