Ireton's regiment was chosen by lot to accompany Cromwell in his Irish campaign. Ireton arrived in Dublin two days after Cromwell on 17 August 1649, with 77 ships full of troops and supplies. Ireton was appointed major-general and after the conquest of the south of Ireland, Lord President of Munster. He went over with John Cook with a brief to reform the law of Ireland, to anglicise it, and to make it a model for a new settlement of English law.

In May 1650 Cromwell was recalled to England to command a Parliamentary force preparing to invade Scotland, and Ireton assumed command of the New Model Army in Ireland with the title and powers of Lord Deputy to complete the conquest of the country. This he proceeded to do, becoming noted as much by the savagery of his methods as for his military skill. By the middle of 1650 Ireton and his commanders faced two problems. One was the capture of the remaining cities held by the Irish Confederate and Royalists forces. The other was an escalating guerrilla war in the countryside as Irish fighters called tories attacked his supply lines. Ireton appealed to the English Parliament to publish lenient surrender terms for Irish Catholics, in order to end their resistance, but this was refused.

His first action after the refusal was to mount a counter-guerrilla expedition into the Wicklow Mountains early in June 1650, to secure his lines of supply for the Siege of Waterford in south-east Ireland. Ireton then blockaded Waterford into surrender by August 1650. Ireton systematically constructed trenches to bring his siege guns within range of the walls and stationed a Parliamentary fleet off the city to prevent it being supplied. Thomas Preston surrendered Waterford after a three-month siege. Ireton then advanced to Limerick by October, but had to call off the siege due to cold and bad weather. Early in 1651 Ireton ordered that areas harbouring the guerrillas should be systematically stripped of food – a scorched earth policy that caused a famine in Ireland by the end of the year. Ireton returned to Limerick in June 1651 and besieged the city for five months until it surrendered in October 1651. At the same time, Parliamentarian forces conducted the Siege of Galway and Ireton rode to inspect the command of Charles Coote, who was blockading that city. The physical strain of his command took hold on Ireton and he fell ill.

After the capture of Limerick, Ireton had dignitaries of Limerick hanged for their defence of the city, including Alderman Thomas Stritch, a Bishop (Turlough O'Brien), Terence Albert O'Brien and an English Royalist officer, Colonel Fennell. He also wanted the Irish commander, Hugh Dubh O'Neill hanged but Edmund Ludlow cancelled the order after Ireton's death.

Ireton fell ill of the plague that was raging through the town and died on 26 November. His loss reportedly "struck a great sadness into Cromwell" and he was considered a great loss to the administration. There are various anecdotes about his demise from Irish ecclesiastical and English royalist sources. Thus, his death has been depicted as divine punishment for the execution of Bishop O'Brien, who prior to his death had called upon Ireton to answer at God's judgment seat for his murders; the Hibernica Dominicana claims that on his death bed Ireton was "privately muttering to himself 'I never gave the aid of my counsel towards the murder of that bishop; never, never; it was the council of war did it… I wish I had never seen this popish bishop'." Philip Warwick stated that among Ireton's last words were "blood! blood! I must have more blood!".

At Ireton's funeral, in Westminster Abbey, John Watson and others wore new tabards that replaced the royal arms with the new arms of the commonwealth.