In the lead up to the Nine Years' War O'Sullivan kept his distance from the rebel cause, but in time he joined a confederation of Gaelic chiefs led by Hugh O'Neill, Earl of Tyrone and Hugh Roe O'Donnell of Ulster. Conflict had broken out in 1594, and O'Neill secured support from Philip II of Spain, who sent a force under the command of Don Juan D'Aquilla in 1601. O'Sullivan wrote to the Spanish king in submission to his authority, but the letter was intercepted by the English. In early 1602 the allied Irish and Spanish forces met the English at the Battle of Kinsale and were defeated.
O'Sullivan resolved to continue the struggle by taking control of the castle of Dunboy. In 1603 English forces attacked Dunboy and the castle fell after a vicious siege. The entire company of defenders was killed in combat or executed.
He was eventually forced to gather up his remaining followers, including women and children, and set off on a long march for the north. He fought a long rearguard action across Ireland, during which the much larger English force fought him all the way, as did rival Irish leaders. The march is one of the most poignant in Irish history and was marked by enormous suffering as the fleeing and starving O'Sullivans sought food from an already decimated Irish countryside in winter, often resulting in hostility, such as from the Mac Egans at Redwood Castle in Tipperary. O'Sullivan marched through Aughrim, where he raided villages for food and met with local resistance. He was barred entrance to Glinsk castle and led his refugees further north. On their arrival at the refuge of O'Rourke's castle in Leitrim, only 35 of the original 1,000 remained, many having died in battles or from exposure and hunger. Others had settled along the route, where their descendants are known to this date as 'the Beres'.
In Leitrim, O'Sullivan sought to join with other northern chiefs to fight the English and organised a force to this end, but resistance ended when Hugh O'Neil successfully sued for peace and swore an oath of loyalty to the crown. O'Sullivan sought exile, making his escape to Spain by ship.
O'Sullivan enjoyed a wide reputation, which helped to open doors for later soldiers from his line. About 165 years later, one descendant served as a general in the American Revolution.