Walker explored the Western Colony of Virginia (present-day Kentucky) in 1750, a full 19 years before the arrival of famed frontiersman Daniel Boone.

[1] Walker married Mildred Thornton (widow of Nicholas Meriwether) in 1741, and acquired land and owned enslaved people in the soon-to be formed Albemarle County from her late husband's estate.

[3] On July 12, 1749, the Loyal Land Company was founded with Walker as a leading member, along with fellow surveyors Joshua Fry and Peter Jefferson, as well as many investors.

After receiving a royal grant of 800,000 acres (320,000 ha) in what is now southeastern Kentucky (which was occupied by Native Americans), the company appointed Walker to lead an expedition to explore and survey the region in 1750, so he set out, probably along the Wilderness Road.

Walker also bought a plantation from Frye along the Hardware River in Albemarle County, in part to pay sums due him for his surveying services.

During some of his expeditions, Walker explored with fellow Virginian, Indian agent, legislator, surveyor and later Revolutionary War general, Joseph Martin, as some of the first colonialists to travel in this area.

[6]: 81 At age 64, Walker again traveled to the western areas of what is now Kentucky and Tennessee; he had been commissioned to survey the border between westward of the Virginia and North Carolina.

In 1775, Walker served as a Virginia commissioner in negotiations with representatives of the Iroquois Six Nations in Pittsburgh, as the colonies tried to engage them as allies against the British.

[9] Because of his broad knowledge of the areas and their resources, Walker became an adviser to Thomas Jefferson from 1780 to 1783 as the future president wrote his Notes on the State of Virginia (1785).