From an ancestor who about a hundred years earlier had married Margaret Bisset, heiress of the district on the Antrim coast known as the Glynns (or Glens), he inherited a claim to the lordship of that territory; and he was one of the most powerful of the Scottish settlers in Ulster whom the English government in the 16th century found difficulty in bringing into subjection.
Many attempts were made to drive them out of Ireland, in one of which, about 1550, Sorley Boy Macdonnell was taken prisoner and conveyed to Dublin Castle, where, however his confinement was brief. The chief rivals of the Macdonnells were the Mac Quillins who dominated the northern portion of Antrim, known as the Route, and whose stronghold was Dunluce Castle, near the mouth of the Bush. Sorley Boy Macdonnell took an active part in the tribal warfare between his own clan and the Mac Quillins; and in 1558, when the latter had been to a great extent overcome, his elder brother James committed to him the lordship of the Route, his hole on which he made good by decisively defeating the Mac Quillins in Glenshesk.
Sorley Boy was now too powerful and turbulent to be neglected by Queen Elizabeth and her ministers, who were also being troubled by his great contemporary, Shane O'Neill; and the history of Ulster for the next twenty years consists for the most part of alternating conflict and alliance jetween Macdonnells and O'Neills, and attempts on the part of the English government to subdue them both. With this object Elizabeth aimed at fomenting the rivalry between the two clans; and she came to terms sometimes with the one and sometimes with the other.
Sorley Boy's wife was an illegitimate half-sister of Shane O'Neill; but this did not deter him from leaguing himself with the government against the O'Neills, if by so doing he could obtain a formal recognition of his title over the lands of which he was in actual possession.
In 1562 Shane O'Neill paid his celebrated visit to London, where he obtained recognition by Elizabeth of his claims as head of the O'Neills; and on his return to Ireland he attacked the Macdonnells, ostensibly in the English interest. He defeated Sorley Boy near Coleraine in the summer of 1564; in 1565 he invaded the Glynns, and at Ballycastle won a decisive victory, in which James Macdonnell and Sorley Boy were taken prisoners. James soon afterwards died, but Sorley Boy remained O'Neill's captive till 1567, when Shane was murdered by the Macdonnells at Cushendun.
Sorley Boy then went to Scotland to enlist support, and he spent the next few years in striving to frustrate the schemes of Sir Thomas Smith, and later of the Earl of Essex, for colonizing Ulster with English settlers. Sorley Boy was willing to come to terms with the government provided his claims to his lands were allowed, but Essex determined to reduce him to unconditional submission.
John Norris was ordered to proceed by sea from Carrickfergus to Rathlin Island, where Sorley Boy's children and valuables, together with the families of his principal retainers, had been lodged for safety; and while the chieftain was himself at Ballycastle, within sight of the island, the women and children were massacred by the English. Sorley Boy retaliated by a successful raid on Carrickfergus and by re-establishing his power in the Glynns and the Route, which the Mac Quillins made ineffectual attempts to recover. Macdonnell's position was still further strengthened by an alliance with Turlough Luineach O'Neill, and by a formidable immigration of followers from the Scottish islands.
In 1584 Sir John Perrot determined to make a further effort to subdue the turbulent chieftain. After another expedition to Scotland seeking help, Sorley Boy landed at Cushendun in January 1585, and his followers regained possession of Dunluce Castle. In these circumstances Sir John Perrot opened negotiations with Sorley Boy, who in the summer of 1586 repaired to Dublin and made submission to Elizabeth's representative. He obtained a grant to himself and his heirs of all the Route country between the rivers Bann and Bush, with certain other lands to the east, and was made constable of Dunluce Castle, For the rest of his life Sorley Boy gave no trouble to the English government. He died in 1590, and was buried in Bonamairgy Abbey, at Ballycastle.
He is said to have married when over eighty years of age, as his second wife, a daughter of Turlough Luineach O'Neill, a kinswoman of his first wife; and two of his five daughters married members of the O'Neill family. Sorley Boy had several sons by his first marriage, one of whom, Randal, was created earl of Antrim, and was ancestor of the present holder of that title.