Hugh Dubh had been chief of the O'Donnells during one of the bitterest and most protracted of the feuds between his clan and the O'Neills, which in 1491 led to a war lasting more than ten years. He left his son to rule Tyrconnel, though still a boy, when he went on a pilgrimage to Rome about 1511. On his return from Rome in broken health after two years' absence, his son Manus, who had proved himself a capable leader in defending his country against the O'Neills, retained the chief authority. When Hugh Dubh appealed for aid against his son to the Maguires, Manus made an alliance with the O'Neills, by whose assistance he established his hold over Tyrconnel. But in 1522 the two great northern clans were again at war.
Conn Bacach O'Neill, 1st Earl of Tyrone, was determined to bring the O'Donnells under his rule. Supported by Munster and Connaught, and assisted also by English contingents and by the MacDonnells of Antrim, O'Neill took the castle of Ballyshannon, and after devastating a large part of Tyrconnel he encamped at Knockavoe, near Strabane. Here he was surprised at night by Hugh Dubh and Manus O'Donnell, and routed with the loss of 900 men and an immense quantity of booty. Although this was one of the bloodiest ever battles between the O'Neills and the O'Donnells, it did not end the war; and in 1531 O'Donnell applied to the English government for protection, giving assurances of allegiance to King Henry VIII.
In 1537 Lord Thomas Fitzgerald and his five uncles were executed for rebellion in Munster, and the English government made every effort to capture Gerald, the heir to the earldom of Kildare, a boy of twelve who was in the secret custody of his aunt Lady Eleanor McCarthy. This lady, in order to secure a powerful protector for the boy, accepted an offer of marriage from Manus O'Donnell, who on the death of Hugh Dubh in July 1537 was inaugurated The O'Donnell. Conn O'Neill was a relative of Gerald Fitzgerald, and this event accordingly led to the formation of the Geraldine League, a federation including the O'Neills, the O'Donnells, the O'Briens of Thomond, and other powerful clans; the primary object of which was to restore Gerald to the earldom of Kildare, but which afterwards aimed at the complete overthrow of English rule in Ireland.
In August 1539 Manus O'Donnell and Conn O'Neill were heavily defeated by the lord deputy at Lake Bellahoe, in Monaghan, which crippled their power for many years. In the west Manus made unceasing efforts to assert the supremacy of the O'Donnells in north Connaught, where he compelled O'Conor Sligo to acknowledge his over-lordship in 1539. In 1542 he went to England and presented himself, together with Conn O'Neill and other Irish chiefs, before Henry VIII, who promised to make him Earl of Tyrconnel, though he refused O'Donnell's request to be made Earl of Sligo.
In his later years Manus was troubled by quarrels between his sons Calvagh and Hugh MacManus; in 1555 he was imprisoned by Calvagh, who deposed him from all authority in Tyrconnel, and he died in 1564. Manus O'Donnell, though a fierce warrior, was hospitable and generous to the poor and the Church. He is described by the Four Masters as "a learned man, skilled in many arts, gifted with a profound intellect, and the knowledge of every science." At his castle of Portnatrynod near Strabane he supervised if he did not actually dictate the writing of the Life of Saint Columbkille in Irish, which is preserved in the Bodleian Library at Oxford.
Manus was married several times. His first wife, Joan O'Reilly, was the mother of Calvagh, and two daughters, both of whom married O'Neills; the younger, Margaret, was wife of the famous rebel Shane O'Neill. His second wife, Hugh's mother, by whom he was ancestor of the Earls of Tyrconnel (see below), was Judith, sister of Conn Bacach O'Neill, 1st earl of Tyrone, and aunt of Shane O'Neill.
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