The Earl supported the Royalist cause of his King, and in 1643 joined with the Duke of Hamilton and the Earls of Lanark and Roxburgh, in opposing the sending of a Scottish army into England to assist the English Parliamentary Army. For this loyalty he received a personal letter from the King. He was appointed Lord Justice General by parliament in 1646. He knew of and is said to have "entered heartily into" the attempted rescue of Charles I in 1648, and was subsequently deprived by parliament of this post on 15 February 1649, under the Act of Classes. The parliament, now being dominant, at the instance of the Public Prosecutor, then passed a Decreet, on 2 March 1650, annulling the original Glencairn Letters Patent of 1488.. Glencairn then led an insurrection in the Highlands in 1653 in favour of King Charles II, when General Monck had possession of Scotland. In January 1654 he was commissioned by Charles II to command the Royal forces in all of Scotland, numbering some 3,500 men, pending the arrival of General Middleton. The insurrection of that year is generally known as "Glencairn's rising", although he later handed his command to Middleton. About this time Glencairn and Lieutenant-General Sir George Munro, 1st of Newmore engaged in a duel with both pistols & swords two miles to the south of Dornoch. Munro had poured scorn on the quality of their forces and Glencairn had defended them, challenging Munro, who lost but was only wounded. Middleton initially placed the Earl under arrest, but the Earl left the army a fortnight later. He was then arrested by Monck in 1655, who later permitted him to return home. Glencairn was excepted from Cromwell's Act of Grace and Pardon.
He was one of the peers whom Monck called to the Convention he summoned when he was about to march into England in 1659. It was at this Convention that Glencairn called for Monck to declare for a free parliament. Upon the Restoration Glencairn waited upon King Charles II at London, when he was again sworn a Privy Councillor and appointed Sheriff Principal of Ayrshire. On 19 January 1661, he was constituted Lord Chancellor of Scotland for life, upon the resignation of the Earl of Loudoun. Glencairn was Chancellor of the University of Glasgow from 1660, and was one of the principal advisors of the re-establishment of Episcopacy in Scotland. He was not, however, opposed to Presbyterianism, and the subsequent bitter disputes between the two religious factions, and particularly against James Sharp, Archbishop of St Andrews, greatly distressed him and affected his health. The Earl died at Belton, East Lothian, on 30 May 1663, aged 54 years. According to some sources he was buried, with great pomp, in the south-east aisle of St. Giles Cathedral in Edinburgh, on 28 July following. He had a daughter, Margaret, who married in 1662, John Hamilton, 2nd Lord Bargany, a descendant of James Hamilton, 2nd Earl of Arran. According to other sources, he was/is not buried in St Giles Cathedral Edinburgh. It was not a burial Church but it does contain memorials of other celebrated Scots. In the old kirkyard, now a carpark, were buried John Knox and William Forbes.
