In the course of a quarrel with his father and his half-brother Hugh, sought aid in Scotland from the MacDonnells, who assisted him in deposing Manus and securing the lordship of Tyrconnel for himself. Hugh then appealed to Shane O'Neill, who invaded Tyrconnel at the head of a large army in 1557, desiring to make himself supreme throughout Ulster, and encamped on the shore of Lough Swilly. Calvagh, acting apparently on the advice of his father, who was his prisoner and who remembered the successful night attack on Conn O'Neill at Knockavoe in 1522, surprised the O'Neills in their camp at night and routed them with the loss of all their spoils.
Calvagh was then recognized by the English government as lord of Tyrconnel; but in 1561 he and his wife were captured by Shane O'Neill in the monastery of Kildonnell. His wife, Catherine Maclean, who had previously been the wife of the earl of Argyll, was kept by Shane O'Neill as his mistress and bore him several children, though grossly ill-treated by her savage captor; Calvagh himself was subjected to atrocious torture during the three years that he remained O'Neill's prisoner. He was released in 1564 on conditions which he had no intention of fulfilling; and crossing to England he threw himself on the mercy of Queen Elizabeth.
In 1566 Sir Henry Sidney by the queen's orders marched to Tyrconnel and restored Calvagh to his rights. Calvagh, however, died in the same year, and as his son Conn was a prisoner in the hands of Shane O'Neill, his half-brother Hugh MacManus was inaugurated The O'Donnell in his place. Hugh, who in the family feud with Calvagh had allied himself with O'Neill, now turned round and combined with the English to crush the hereditary enemy of his family; and in 1567 he utterly routed Shane at Letterkenny with the loss of 1300 men, compelling him to seek refuge with the MacDonnells of Antrim, by whom he was treacherously put to death.
In 1592 Hugh abdicated in favour of his son Hugh Roe O'Donnell (see below); but there was a member of the elder branch of the family who resented the passing of the chieftainship to the descendants of Manus O'Donnell's second marriage. This was Niall Garve, second son of Calvagh's son Conn. His elder brother was Hugh of Ramelton, whose son John, an officer in the Spanish army, was father of Hugh Baldearg O'Donnell (d. 1704), known in Spain as Count O'Donnell, who commanded an Irish regiment as brigadier in the Spanish service. This officer came to Ireland in 1690 and raised an army in Ulster for the service of James II, afterwards deserting to the side of William III, from whom he accepted a pension.