The religious wars of Elizabeth were attended by rebellions of the Irish Roman Catholics. James Fitzmaurice Fitzgerald, a member of the great House of Geraldine that ruled over the larger part of Munster, landed at Dingle Bay in 1579 with a papal army poised to restore Roman Catholicism in Ireland. When he was killed soon after, leadership of the revolt passed to his cousin Gerald Fitzgerald, 14th Earl of Desmond, who was finally defeated in 1580 after a bloody struggle. The defeat of the Desmond rebellion paved the way for a plantation scheme in Munster, as much of their lands were confiscated and allocated to private English settlers. In spite of the colony's temporary overturn during the O'Neill wars of the late 1590s, the plantation established a wealthy and influential Protestant minority in Munster. 

From 1594 to 1603 Ireland was engulfed in the Nine Years' War, also known as Tyrone's Rebellion, which originated in Ulster but gained the support of Gaelic lords throughout the country. Hugh Roe O'Donnell first rose in open revolt in Donegal in 1594, and was joined by his father-in-law Hugh O'Neill, 3rd Baron of Dungannon and 2nd Earl of Tyrone. 

In 1598 O'Neill annihilated an English army at Yellow Ford on the River Blackwater in Armagh and fended off Robert Devereux, 2nd Earl of Essex, whom Elizabeth had sent against him, thereby directly or indirectly gaining control of most of the country. In 1601 O'Neill was defeated at the Battle of Kinsale by Charles Blount, Lord Mountjoy, and two years later he was compelled to submit by the Treaty of Mellifont.

During the war the greatest cruelty and treachery were practised on both sides. In order to destroy Irish resistance, the English devastated villages, crops, and cattle, putting many people to death. The greater part of Munster and Ulster was laid desolate, and more inhabitants died from hunger than from war.