The American War of Independence was the culmination of the civil and political American Revolution. In the 1760s, a series of acts by Parliament was met with resistance in the Thirteen Colonies in America. In particular they rejected new taxes levied by Parliament, a body in which they had no direct representation. The colonies had previously enjoyed a high level of autonomy in their internal affairs and viewed Parliament's acts as a denial of their rights as Englishmen.[58] Armed conflict began between British regulars and colonial militiamen at the Battles of Lexington and Concord in April 1775. The Second Continental Congress sent petitions to the Crown for intervention with Parliament, but the King and Parliament ignored them. George declared the American leaders to be traitors and a year of fighting ensued. Thomas Paine's book Common Sense referred to George III as "the Royal Brute of Great Britain".

The colonies declared their independence in July 1776, listing twenty-seven grievances against the British king and legislature while asking the support of the populace. Among George's other offences, the declaration charged, "He has abdicated Government here ... He has plundered our seas, ravaged our coasts, burnt our towns, and destroyed the lives of our people." The gilded equestrian statue of the King in New York was pulled down. The British captured the city in 1776 but lost Boston, and the grand strategic plan of invading from Canada and cutting off New England failed with the surrender of British Lieutenant-General John Burgoyne following the battles of Saratoga.

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In the later part of his life, George had recurrent and eventually permanent mental illness. The exact nature of the mental illness is not known definitively, but historians and medical experts have suggested that his symptoms and behaviour traits were consistent with either bipolar disorder or porphyria.