In May 1642, the Roman Catholic clergy of Ireland convened at Kilkenny to discuss ways of controlling the Irish Uprising and of achieving national unity against the Protestant invaders. With representatives of the Irish rebels and the "Old English" aristocracy in attendance, an alternative government for Ireland was proposed. Asserting their loyalty to King Charles, the Confederates drew up an Oath of Association, similar in intent to the Scottish National Covenant, in which they swore to restore Catholicism to a reunited Ireland.

The first Confederate General Assembly was held at Kilkenny in October 1642. A constitution was drawn up by lawyer Patrick Darcy in consultation with noblemen and clergy. A Supreme Council of 24 members was elected, with Lord Mountgarrett as president, and a bureaucracy for the civil, legal and military administration of Ireland was established. Money was authorised to be minted and arrangements for collecting taxes were put in place. Confederate ambassadors were appointed to Paris, Madrid and the Vatican, from where it was hoped that money and weapons would be supplied to continue the Confederate War that had developed from the 1641 uprising. Meanwhile, four regional military commands (Ulster, Leinster, Munster and Connacht) were formed to direct the war.

The Assembly met annually at Kilkenny until 1648. Although a sophisticated parliamentary system began to emerge, the Assembly never succeeded in gaining full control over Ireland's administrative structure like the Parliamentarians in England or the Covenanters in Scotland. Roman Catholics regarded the Confederacy as a means of restoring the Catholic Church to its former power in Ireland and in 1645, Pope Innocent X sent Archbishop Rinuccini as Papal Nuncio to Kilkenny. Rinuccini was instructed to work for the expulsion of all Protestants from Ireland. While O'Neill and the native Gaelic rebels supported Rinuccini, most of the Anglo-Irish aristocracy regarded the Pope's demands as unrealistic and worked for a negotiated religious settlement with King Charles. Rinuccini's refusal to compromise in negotiations with the King's deputy, the Protestant Marquis of Ormond, opened deep divisions within the Confederacy.

The Confederacy was formally dissolved under the terms of the Second Ormond Peace in January 1649, which was negotiated by the Marquis of Ormond and secured an alliance between the Confederates and the Royalists. News of the Second Ormond Peace, coupled with the arrival of Prince Rupert's fleet at Kinsale in February 1649, greatly alarmed the English Parliament. One of the earliest acts of the Commonwealth Council of State after the execution of King Charles was to appoint Oliver Cromwell commander of an expeditionary force for the final subjugation of Ireland