William Mayo was the eldest child of the well-to-do family of Joseph and Elizabeth (Hooper) Mayo. At the age of twenty-five he left England, accompanied by his younger brother Joseph, to seek his fortune in Barbadoes, where a cousin had settled some time earlier. There he established himself as a surveyor. In 1717 Mayo received a commission to make a map of Barbadoes, which he accomplished with such skill that Governor William Tryon (North Carolina) urged the English Board of Trade to purchase it and to grant Mayo a patent enabling him to sell his map on a commission basis. The map also gained him election to membership in the Royal Society of London.
Mayo remained in the West Indies for ten years. It was in about 1719 that Mayo, now nearly forty years of age, with his wife and four daughters and with his fortune already made and assured, began to consider moving permanently to Virginia. Finally, in 1723, with his own family and the families of two brothers and a cousin, he arrived in the Virginia.
In 1736, a commission of six men sent a surveying party under Mayo's leadership to explore Lord Fairfax's territory (Virginia), one of three such parties outfitted at that time. This first survey of Fairfax's domains provided the first useful map of the region, and Mayo's journal provided most of the knowledge available to first settlers who were then breaking through the Blue Ridge gaps into western Virginia territory.
Together with Professor Alexander Irvin, Mayo was also responsible for setting the boundary between Virginia and North Carolina. One of the rivers intersecting the line was named the Mayo River in his honor.
In 1737, Mayo laid out the city of Richmond, Virginia.
Mayo served as the chief civil engineer in Virginia until his death in Richmond in 1744.