Mayo attended subscription schools until he enrolled to Kentucky Wesleyan College in Millersburg.

While attending college, Mayo had realized the potential of coal and other mineral deposits in the Big Sandy Valley.

Mayo formed a real estate company in 1888 that specialized in acquiring land and mineral rights in Eastern Kentucky and Southwestern Virginia.

After he displayed coal from his land at the Chicago's World Fair, a wealthy businessman named Peter L. Kimberley purchased $10,000 in the company's holdings.

This money was used to further expand the land and mineral rights owned by the Paintsville Coal and Mining Company.

Mayo had originally planned a modest twenty room house, but following trips to the Bluegrass region of Kentucky, and having in 1904 acquired Varina Farms, the Powhatan Plantation in Mayo's ancestral Virginia, he decided to build a mansion which would rival those he had seen.

The construction crews filled in the swampy area and then went to work on building the foundation for the estate.

The stone columns surrounding the exterior of the mansion were each transported through the creek during dry periods on sleds pulled by twenty-oxen teams.

Originally, light was to be provided in the mansion by using carbide gas, but near the end of construction, Paintsville received electrical service.

Bright's Disease had attacked the function of the liver, but news reports were still hopeful for a quick recovery.

On March 1, 1914, Mayo was taken by special train to the Jewish Hospital in Cincinnati, where an entire floor was occupied.

In late April, Mayo was finally moved to the Waldorf Astoria in New York City where another group of specialists were in wait to care for him.

The governor of the Commonwealth, James B. McCreary, brought a delegation of state officials to Mayo's funeral.