He began in politics as a member of the Glasgow University Labour Club, before deciding to help form the Glasgow University Scottish Nationalist Association (GUSNA) in 1927. MacCormick was often known by his nickname "King John", which he said came from a heckle during a debate he was participating in when upon a question from the floor whether a devolved Scotland would retain the monarchy or be a republic someone interjected and said that, "no, it will be a kingdom and John MacCormick will be our king."
He then helped to form the National Party of Scotland in 1928 before leading them into a merger with the Scottish Party in 1934 to found the modern Scottish National Party (SNP). He resigned from the party in 1942 following his failure to persuade the party to adopt a devolutionist stance rather than supporting all out Scottish independence and due to the victory of Douglas Young over his favoured candidate William Power for the chairmanship of the party. Along with a number of dissatisfied delegates to that year's SNP conference he established the Scottish Convention to campaign for home rule for Scotland.
He was elected Rector of the University of Glasgow in 1950 as GUSNA's candidate, serving until 1953. This association with GUSNA also saw the formation of a political friendship with a then young law student at Glasgow University, Ian Hamilton, who had run his campaign to be elected rector.
He was involved, along with Hamilton, in the removal of the Stone of Destiny from Westminster Abbey on Christmas Day 1950 and its return to Arbroath Abbey. He was also responsible, again along with Hamilton, for MacCormick v. Lord Advocate, the constitutional challenge over Queen Elizabeth using the title the second, rather than the first in Scotland -- there having been no Elizabeth I of Scotland.
In the 1950s he formed the Scottish Covenant, a non-partizan political organisation which campaigned to secure the establishment of a devolved Scottish Assembly. This covenant was hugely successful in securing support from across the political spectrum as well as in capturing the Scottish public's imagination (over 2 million signed a petition demanding the convocation of an Assembly). However, in the longrun it proved unsuccessful in establishing the Assembly MacCormick so craved, and it would not be until nearly 40 years after his death until Home Rule would be secured.
In 1955 MacCormick had a book detailing his activities in the home rule movement published, entitled The Flag in the Wind.
His son Iain served as SNP Member of Parliament for Argyll from 1974 till 1979, and his second son Neil was Professor of Law and Vice-Principal of the University of Edinburgh and elected an SNP Member of the European Parliament in 1999. His family came from Mull, and he was related to the Scottish Gaelic novelist of the same name.