A party of scouts explored the future Amherst area in 1742, preceding the development of the Hat Creek Presbyterian Colony, in present Campbell County. They found only one aged white man, possibly Hughes, living within a 45-mile radius. According to a local history, "the region was inhabited by Indians who disputed its possession and offered combat with the whites from the very first. Some were of the Sapon (Saponi) nation but most of these red men wale of the Tuscaroras tribe and were commonly known as Monacans."

In the 1750s, Thomas Jefferson described a party of passing Indians on his property (near Monticello) who visited a burial mound there, called' Monasukapanough. They stayed at the mound for quite some time, with expressions of sorrow on their faces, and then they returned to "the high road" and went on their way. Because the Monacans of Amherst County ware the only Siouan Indians remaining in the mound region at this time, it is assumed that they were these travelers. The episode shows that the Monacan people knew their ancestors were buried in the mounds and still visited them to grieve. Jefferson later excavated this mound, finding numerous graves inside.

Lewis Evans published a map, in 1755, showing the Monacans and Tuscaroras located in the Amherst, Nelson and Bedford areas. By 1757, John Lynch was living at the "old Ferry House" on the James River. There were two villages of Monacan Indians located nearby, one on Judge Winston's property near White Rock Hill and one on the opposite side of the river, near what is now Madison. These Indians were peaceful and did not harm their new neighbors, the settlers.

However, other Monacan people were disturbed by the arrivals. According to local sources, "as late as 1758 they (Monacans) were to prove so troublesome to the Quakers at Goose Creek (near Bedford) that the settlement had to be abandoned for two years before being reclaimed." Another source states, "It is quite possible that this can be explained by the Quakers choosing for settlement one of the best known Indian east and west Blue Ridge trail crossings and also their site was near an Indian burying ground of some significance."

By the 1770s, a number of new settlers had chosen to stay in the area now called Amherst. Among them were Robert Johns, who first patented land in 1758, and Thomas Evans, who died in 1774 and gave his lands to his son, Benjamin. These men were ancestors of the modern Monacan Nation, having married Indian women from the area. Benjamin Evans' children settled on Johns Creek in Amherst.

The Revolutionary War began during this time, and several Monacan forefathers served in it. When the war was over, the new government commissioned the First National Census in 1782. Benjamin Evans was listed as a white man with six mulatto children, and Robert Johns and his family were listed as well. Tax records show that both of these ancestors owned slaves.

The Town of Lynchburg was established in 1786. Prior to this, a settlement had developed at Bethel, on the James River, and both Indian and white people were known to live there. According to one source, "It is common knowledge among older people of the area that the graveyard (at Bethel) contains a mixture of Whites and Indians who have lived in the vicinity for the past two centuries."

In 1790, William Johns, listed as a "free man of color," married Molly Evans, and Ned Branham married Molly's sister, Nancy Evans. William Johns was sometimes called "Portugue" because of his broken English. It has been suggested that William spoke an Indian language and never learned to speak English without an accent.

By 1807, the settlement of Monacan ancestors on Johns Creek had been named "Oronoco," ail== a type of dark-leaf tobacco grown in the area. One source has suggested that the Indians helped their new neighbors to grow this tobacco, thus contributing greatly to one of the greatest tobacco markets in the world at that time, which became the City of Lynchburg. The settlement at Oronoco was listed as a post town on a map of the county, and from this settlement grew the modern Monacan Nation.