However conflict broke out again in 1642 when Charles tried to arrest 5 members of Parliament who had been actively disagreeing with his policies. The MPs fled into the back streets of London but when the King went after them, the citizens expelled him angrily from their city. This was a direct violation by the people of the supreme power of the King and marked the beginning of the English Civil War.

Those English who supported the King (the Cavaliers) had support in north England and Wales and the Parliamentarians (Roundheads) had support in the rest of England. Despite the fairly even start, however, the Cavaliers were fought back and in 1646 the Roundheads forced the King to surrender. However, at the ceasefire negotiatons Charles would not agree to the Roundhead terms and after a stalemate the war erupted again in 1648. Once again the Cavaliers were defeated but this time the Roundheads did not accept a surrender and instead captured and executed Charles in 1649. Thus England found itself with no King. For the next 11 years England was a Republic of sorts. It was ruled from 1653 to 1658 by a general named Oliver Cromwell, who was was a fundamental Protestant but an extremely cruel man. He was given the title 'Lord Protector of the Commonwealth of England', but he had been active in Ireland long before he undertook that role:

In 1641, just prior to the Civil War, the Irish of Ulster had begun an uprising and attacked the planters who had been settled 30 years before. Between 10,000 and 15,000 Protestant planters were murdered by the Irish at places such as Portadown. Due to the war, the English did nothing about this and the death-toll became heavily exaggerated over time. In 1649, after the Civil War had ended, Cromwell landed at Dublin with 12,000 men with the intention of punishing those who had uprisen. He first attacked Drogheda and captured it, killing over 3000 people. He then marched on Wexford town and massacred several hundred people there. The surrounding towns of Cork, Bandon, Kinsale and Youghal surrendered. Cromwell left Ireland in 1650 having dealt a severe blow to the uprising Irish.

A problem of equal concern to Cromwell after the Civil War, however, was the fact that most of the soldiers in the Roundhead army still needed paid for their time served in the Civil War, but Parliament had no money to give them. So Cromwell decided to pay them in land. He forcibly moved thousands of Irish from their homes in Munster and Leinster and resettled them in counties Clare, Galway, Mayo and Roscommon. This was by far the poorest land in Ireland and, as well as this, they were not allowed to live within 3 miles of the coast. This strip, called the 'Mile Line' was given to Cromwell’s soldiers. In 1652 the newly cleared land in Munster and Leinster was given to Protestants in what was called the 'Cromwellian Settlement'. There was now no part of Ireland where Catholics owned more than ½ of the land. The main reason for this was Cromwell's belief in fundamental Protestantism and hatred of Catholicism. He claimed to be acting on God's behalf and expelled about 1000 Catholic priests from Ireland.

In 1660, Cromwell died and was buried in state in Westminster Abbey in London. However, unable to find a suitable successor as Lord Protector, Parliament reinstated the monarchy with Charles 2nd, abeit with carefully reduced powers. Although Charles relaxed the anti-Catholic laws that Cromwell had introduced, he didn't make any attempt to reverse the land confiscations that had taken place over that period in Ireland. He had Cromwell's body exhumed, hung, decapitated and the body thrown in a latrine [toilet]. His head was put on a post where it remained until a storm finally dislodged the skull over 50 years later.