Waterford had committed itself early. When the Irish Rebellion of 1641 began and Protestant refugees displaced by the insurgents started arriving in town, the city's mayor wanted to shelter them. The recorder and several aldermen on the city council wanted to expel them and let in the rebels. By March 1642 the rebel faction had won, and the Protestants of Waterford were put on ships to England, often after their property had been looted by the city mob. The city's Catholic identity hardened. In 1646 a synod of Catholic bishops, meeting in Waterford, excommunicated any Catholic who supported a treaty between the Confederates and English Royalists that did not guarantee free practice of the Catholic religion. When Cromwell finally arrived three years later, he was approaching the most intransigent Catholic city in southeastern Ireland.

Cromwell could not bring his heavy siege guns up to Waterford by sea because the fort at Duncannon, commanding the river approach, held out under Edward Wogan from 15 October to 5 November despite a determined Parliamentarian assault. New Ross surrendered on 19 October, Carrick-on-Suir on 19 November, and a 24 November counter-attack by Ulster Irish troops left 500 of them dead. Cromwell isolated Waterford from the east and north, but the city still had access to reinforcements from the west, and up to 3,000 Irish soldiers from the Confederate Ulster Army poured in under Richard Farrell. Farrell had been a successful officer in the Spanish army and was experienced in siege warfare from the battles in Flanders. The weather turned brutally cold and wet. Disease swept the Parliamentarian camp. Of the 6,500 soldiers who began the siege, only about 3,000 remained fit when Cromwell finally called it off on 2 December and retreated to winter quarters at Dungarvan. Among his casualties was his second-in-command, Michael Jones, dead of disease.

Waterford was not closely besieged again until July 1650, but the intervening months were a slow strangulation. In January the city's western supply line was cut. In June, Henry Ireton -- Cromwell's son-in-law -- arrived before the walls. By then Thomas Preston commanded the garrison, but he was sick, and so was much of the city. An epidemic, believed to be bubonic plague, was killing up to 400 people a week inside the walls. The fall of Carlow in July cut off resupply via the River Barrow. Ireton ordered trenches dug to bring his siege guns within range and blockaded the port with a naval fleet. By the end of July the artillery was in position. Preston had 700 fit troops, 500 pounds of gunpowder, and an outbreak of plague. On 6 August 1650 he surrendered Waterford to Ireton. His soldiers were allowed to march away to Galway or Athlone, but everything else -- the artillery, the ammunition, the ships in the harbour -- stayed behind.

Ireton was a different man from his father-in-law, or perhaps just calculating differently. He granted the civilian population lenient surrender terms, respecting their lives and property. The contrast with what would happen at Limerick the following year is striking: there, Ireton would have the most energetic defenders hanged. How many of Waterford's garrison and population died during the two sieges is impossible to determine. What is certain is that Waterford was the last Irish Catholic stronghold in the east of Ireland to fall to the Parliamentarians. After its surrender, Irish Catholic forces held only an enclave in Connacht, west of the Shannon. The city walls Farrell had defended so well still stand in long stretches today, and Waterford retains more of its medieval defenses than any Irish city except Derry.