There is no liberty, if the power of judging be not separated from the legislative and executive powers.

Middleton opposed declaring independence from Great Britain and resigned from the Second Continental Congress in February 1776 when more radical delegates began pushing for independence. He served as that body's president during the last few days of the First Continental Congress following the departure of Peyton Randolph. His grandson also named Henry (1770–1846) had a long career in politics.

After his capture by the British in 1780 he accepted defeat and returned to the status of a British subject until the end of the war. A member of the colonial legislature during the American Revolution he attended the Continental Congress and served as that body's presiding officer for a few days in 1774.