Between 1566 and 1568, the politics of the British mainland were turned upside down by the disintegration of Mary's personal rule. The Scottish kingdom was rocked by the murders of Riccio and Darnley, the Bothwell marriage, Mary's enforced abdication, the defeat at Langside and finally her catastrophic flight into England. These events splintered Scottish national politics, leaving a divided country slipping into civil war. For Argyll they also brought the bitter split with Moray, his close friend and political partner. At the start of 1566, Mary, Queen of Scots was dominating mainland Britain and threatening the English queen. By 1568 she was a fugitive in England begging Elizabeth for assistance. This dramatic reversal of fortunes shifted the balance of power within the mainland, leading to a major re-alignment of British politics.

The immediate consequences of Argyll's abandonment of an integrated British policy were felt within the Gaelic political world. With the loss of the triangular British link, the 5th earl severed the automatic connexion between his Ulster policies and Anglo-Scottish amity. Instead of co-operating with the English in Ireland, he treated the Dublin and London administrations as a foreign power with whom he needed to bargain. Within Ulster, the idealism of Argyll's British policy was replaced by the pragmatic goal of maintaining his Gaelic dependants. In particular, by re-establishing MacDonald power, he sought to stabilise the North Channel area. He then masterminded a momentous Ulster alliance, binding together the MacDonalds, O'Neills and O'Donnells.