The English feared the formation of a fifth column (in league with the Ulster clans of O'Neill and O'Donnell), which might lay the foundation of a Bruce-style invasion of Ireland, and the clan did spread into the adjacent territories of Clandeboy and the Route. This migration from Scotland was cemented when the king's successor, James V, chose to maintain favourable relations with the rival Campbell clan, although he did swing around to favour the MacDonnells in the 1530s, restoring certain lands to them in Kintyre and Islay while encouraging their expansion in Ireland. This period of royal favour ended with the defeat in 1539 at Belahoe of a combined Irish force (including the MacDonnells) by an English army: Scottish plans for an invasion of Ireland were then put off, while the French invasion of England that King Henry VIII had feared failed to occur.
On his release, Sorley Boy received a large ransom after seizing the constable of Carrickfergus Castle, and went on to subjugate the MacQuillans. This clan was the immediate rival of the MacDonnells in Ireland, dominating the northern portion of Antrim - the Route - with their stronghold at Dunluce Castle, near the mouth of the river Bush. In 1558, the MacDonnell chieftain committed to him the lordship of the Route upon the death of his brother Colla, and Sorley Boy promptly raised a force of troops on the Scottish coast to confront the MacQuillans. He landed at Marketon Bay in July 1559, where the MacQuillans were strongly posted at the foot of Glenshesk, and attacked them at Beal a Faula, driving them south with heavy losses.
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. For the next twenty years, the history of Ulster consists for the most part of alternating conflict and alliance between 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; she came to terms sometimes with the one and sometimes with the other. One event that simplified the situation for the queen was the success in 1560 of the Protestant revolution in Scotland, which largely removed the threat of invasion her father had suffered in 1539. But complications were never wanting in Ulster, owing to the criss-cross of dynastic and political allegiances and betrayals. At this time Shane O'Neill was allied by marriage with the Campbells, the MacDonnell clan's chief rival in Scotland; yet Sorley Boy's wife was an illegitimate half-sister of the same Shane.
James died soon afterward, but Sorley Boy remained O'Neill's captive until 1567, during which period he seems to have won his captor's confidence. After his unexpected defeat by the O'Donnells in the battle of Farsetmore, O'Neill turned to the MacDonnells for assistance and attended a feast laid on by them at Cushendun, bringing with him out of captivity Sorley Boy and his late brother's widow, Agnes, in order to secure an alliance with the Scots. In an event which seems to have had the approbation of the lord deputy of Ireland, Henry Sidney, O'Neill was stabbed and murdered by his hosts. Sorley Boy visited Scotland immediately and returned to Marketon Bay with 600 redshanks, in whose presence he swore never to leave Ireland.
In 1569, an alliance between the O'Neills and MacDonnells was secured upon the marriage on Rathlin Island of Shane's successor, Turlough Luineach O'Neill, to the widow Agnes. Sorley Boy 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. (See Plantations of Ireland for details). He was willing to come to terms with the government provided his claims to the lands were allowed, but Essex determined to reduce him to unconditional submission. After a retreat into Scotland, Sorley Boy returned and made an unsuccessful attempt on the crown garrison at Carrickfergus. In time, he did come to terms with Smith, who supported his claims to title in the Route on condition that he take up the reformed religion. In 1573, letters of denization were addressed to Sorley Boy from the crown, but Essex frustrated these with the renewal of his plantation scheme; still, Sorley Boy managed to hold his position, when Essex failed in his negotiation with the Scottish regent and the Earl of Argyll of a withdrawal of the Scots from Ulster.
Essex then switched tack, having struck a deal with Turlough Luineach, and defeated Sorley Boy around Castle Toome, where the Bann flows out of Lough Neagh. Essex had to withdraw to Carrickfergus for lack of provisions, but he then ordered a follow-up operation, with the intention of driving the Scots from Ulster. Under the commands of John Norreys and Francis Drake an amphibious strike force proceeded 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 (perhaps 700) were massacred by the English. Sorley Boy retaliated with a successful raid on Carrickfergus, in which the garrison broke before a highland charge, and managed to re-establish his power in the Glynns and the Route, which the Mac Quillans made ineffectual attempts to recover.
On surveying the results, Lord Deputy Sidney agreed to a ceasefire, although he supported the claims of the MacQuillans to the Route, and of Sorley Boy's nephews (sons of the widow Agnes) to possession of the Glens - a typical Campbell manoeuvre, effected through their alliance with Turlough Luineach. At the same time, Sidney forwarded to London Sorley Boy's petition for title, although it sat there without response for years. With fortitude, the MacDonnells managed to strengthen their position through an alliance with Turlough Luineach, and by a formidable immigration of followers from the Scottish Isles.
Having made his submission, Sorley Boy at last obtained a grant to himself and his heirs of the greater part of the Route country, between the rivers Bann and Bush (an area then called the Boys), with certain other lands to the east, and was made constable of Dunluce Castle. A month beforehand, Sorley Boy's nephew had received a grant in similar terms of the greater part of the Glynns. At the same time, in the Treaty of Berwick (1586) , a clause was inserted recognising the right of the clan MacDonnell to remain in Ireland.
Sorley Boy gave no further trouble to the English government, although he did assist survivors of the Spanish Armada to escape Ireland in 1588 (see Girona). He died in 1590 at the very place of his birth, the Castle of Dunanynie, and was buried in the traditional place of the MacDonnells, Bonamairgy Abbey at Ballycastle.