Johnson was born c. 1740, in Ireland, and may have been a nephew of Sir William Johnson. Guy was the son of either John or Warren Johnson of Smithstown, Dunshaughlin, Co. Meath, each younger brothers of Sir William Johnson. The Johnsons were descendants of the O'Neill dynasty of Ireland.
Coming to America at an early age, Johnson was in the Mohawk Valley by 1756. He served throughout the French and Indian War, a part of the time as secretary to Sir William. He also held a commission as lieutenant in one of the New York independent companies and commanded a company of rangers under General Amherst in the campaign of 1759-1760. Following the war, he was for a time colonel and adjutant general in the New York Militia.
In 1762, he was appointed "Deputy for the Six Nations and Neighbouring Indians, " under Sir William. As deputy agent he attended many Indian councils, serving occasionally as secretary to the Superintendent, and sometimes acting for him during his absence. Great confidence was reposed in him, both by Sir William and by the Indians themselves. In 1763 he established his residence at Guy Park, near Amsterdam, New York. He was elected to the New York assembly for the term 1773-1775. Upon the death of his father-in-law in 1774, he was directed by General Gage to assume the duties of superintendent of the northern department for the time being, the appointment being later confirmed from England. Immediately upon the outbreak of revolutionary disturbances the following year, Johnson invited the cooperation of the Six Nations in the British cause and fortified Guy Hall, but in the latter part of May he retired to Lake Ontario, where he assembled a large number of Indians and secured their promises of assistance.
In July 1775 he proceeded to Montreal, accompanied by some Indians and 220 rangers. He organized the Indians in that vicinity and for a time assisted in the defense of St. John's. In the following winter he visited England, but returned to America in the summer of 1776, arriving at Staten Island on July 29. It was his purpose to further military cooperation between the Indians and British on the New York frontier, but he was able to accomplish little. In September 1778, he at last left New York for Quebec but, being obliged to winter at Halifax, did not reach his destination until July 1779. He then proceeded by way of Montreal to the upper country, and was with the British and Indians at the battle near Newtown, New York, in August 1779. During the ensuing two years he made his headquarters at Niagara, and incited the Indians to raiding expeditions along the back settlements. He was succeeded in his position as superintendent in 1782 by Sir John Johnson.
After the Revolution Johnson, like many Loyalists, went to England, where he endeavored to secure compensation for the losses sustained by the confiscation of his estates. He died in London in 1788.
Johnson is best remembered for his actions as British Superintendent of Indian Affairs. He claimed credit for having inspired the raid which culminated in the Wyoming massacre. He also helped to provide for the many Iroquois refugees made homeless by the Sullivan Expedition that year, which laid waste to their villages and food stores in western New York.
A not too sympathetic contemporary observer described Johnson as "a short, pursy man, of stern countenance and haughty demeanor, " adding, "His voice was harsh, and his tongue bore evidence of his Irish extraction. "
On 1763, Guy Johnson married Sir William Johnson's daughter Mary (Polly), one of his children by his first consort, Catherine Weisenberg. His uncle (now also father-in-law) gave them a square mile of land on the Mohawk River, but later the family had to go to Canada to settle near Fort Niagara. On the way, Polly Johnson died at Oswego.
