Argyll inherited his title and the leadership of the Campbell clan in 1638. Later that year he emerged as the leader of the Scots opposed to the religious policies of Charles I.
After negotiating the Treaty of Berwick in 1639 he helped to make the Scottish Parliament an effective political body. Later that year Argyll arranged for his main political opponent, Earl of Montrose, arranged for him to be confined in Edinburgh Castle.
In August, 1644, the Earl of Montrose defeated the Covenanters under Lord Elcho at Tippermuir. He then captured Aberdeen (September, 1644) and plundered the countryside. At Inverlochy (February, 1645) his army killed 1,500 Campbells in battle. He achieved further victories at Auldearn (May, 1645) and Alford (June, 1645). Argyll was therefore pleased when Montrose was defeated by David Leslie at Philiphaugh (September, 1645).
In July, 1650, the Parliamentary army invaded Scotland. Cromwell's victory at Dunbar in September destroyed Argyll's authority and he was forced into retirement.