During the Civil War he declared for Parliament and served in the Earl of Manchester's army. He fought in many of the major battles of the war and joined the New Model Army in 1645. By the end of the conflict he had risen to the rank of Major-General and was a noted friend and supporter of Oliver Cromwell.
He was elected to the Long Parliament for Wendover in 1646. When conflict resumed he was wounded at Appleby in July 1648. He had to return to London but was well enough to command the escort that brought the King to London in January 1649. Harrison sat as a commissioner (judge) at the trial and was the seventeenth of fifty-nine commissioners to sign the death warrant of King Charles I.
In 1650, Harrison was appointed to a military command in Wales where he was apparently extremely severe. He was promoted to the rank of Major-General in 1651 and commanded the army in England during Cromwell's Scottish expedition. He fought at the battle of Knutsford in August and at Worcester in September 1651.
By the early 1650s Harrison was associated with the radical Fifth Monarchists and became one of their key speakers. He still supported Cromwell and aided in the dissolution of the Rump Parliament in April 1653. Harrison was a radical member of the Nominated Assembly (Barebones Parliament) that replaced the Parliament. When the Assembly was dissolved, Harrison and others refused to leave and had to be forced out by soldiers. Harrison was dismissed from the Army in December.
After Cromwell's death Harrison remained quietly in his home, supporting none of the contenders for power. Following the Restoration, Harrison declined to flee and was arrested in May 1660, tried in October, and was the first of the Regicides to be executed by being hanged, drawn and quartered on October 13, 1660.
Samuel Pepys wrote an eyewitness account of the execution at Charing Cross, in which Major General Harrison was dryly reported to be "looking as cheerful as any man could do in that condition". This account is also quoted on a large plaque on the wall of the Hung, Drawn and Quartered public house near Pepys Street, where the diarist lived and worked in the Navy Office.