The area that would become Cherokee County was explored by Spanish conquistador Hernando DeSoto as early as 1540.

[6] Early white farmers who wed Native Americans were granted property along the Nottley River in 1817.

[8] European Americans began to settle near present-day Murphy and a trading post was established prior to 1828.

The two-story log cabin built by Thomas Tatham is the oldest surviving structure in the county.

[16] Cherokee County's first industry, a tannery northeast of what would become Andrews, was established by James Stewart in 1852.

[17] As European-American population increased in the area in the 19th century, the state legislature created new counties.

Harshaw Chapel, the oldest brick structure and church building in Cherokee County, was constructed in 1869.

In the 1870s, the Valentine brothers of Richmond, Virginia, caused extensive damage to at least eight ancient mounds in Cherokee, Haywood, Jackson, and Swain counties.

They roughly excavated and looted them, seeking artifacts for the museum of their father, Mann S. Valentine, which he operated in Richmond.

The hospital was a two-story white brick building atop a hill on Peachtree Street in downtown Murphy.

[27] The 22-bed Murphy General Hospital was built by Dr. F. V. Taylor in 1941 and closed in July 1969 due to insufficient staff and property.

[30][31] In January 1974 the Murphy Town Council approved spending $4,000 on a study to see whether constructing a new hospital was feasible.

[32] Citing uncollected payments, District Memorial Hospital declared bankruptcy in 2000, closed soon afterward, and was demolished.

[40] In the early 1940s, religious tourist attraction Fields of the Wood opened in western Cherokee County with the world's largest Christian cross and biggest Ten Commandments, covering a mountainside.

[41] Cherokee County's only animal shelter, Valley River Humane Society, was founded in Marble in 1969.

[43] An F4 tornado in western Cherokee County killed four people (including two children) and injured 40 on April 3, 1974.

[46] The Cherokee County Historical Museum was founded in 1977 and occupies a former Carnegie Library building in downtown Murphy.

[48] A proposal to open a 1,200-acre state park at the site was dismissed by the North Carolina Department of Natural and Cultural Resources in 2023, as officials said the project would cost more than $20 million.

As of 2023, the tourism industry employs at least 590 people in the county and generates more than $100 million in annual visitor spending.

[51] Located in the southern Appalachian Mountains, Cherokee County contains a varied natural landscape.

Thirteen are classified as high-hazard, meaning a dam failure may be deadly; nine of those have no emergency action plans.

[53] In April 1974, parts of Cherokee County were affected by a historic weather event, the 1974 Super Outbreak of tornadoes.

This affected parts of 13 states and was the second-largest such event to be recorded in the U.S. Portions of the Qualla Boundary are located in Cherokee County.

The land is exclusive territory of the federally recognized Eastern Band of Cherokee Indians and is protected by their Tribal Police.

Mandated by the laws of the State of North Carolina, Cherokee County is governed by an elected five-member board of commissioners who each serve a four-year term.

The commission, as of 2023, is composed of Ben Adams, Dr. Dan Eichenbaum, Jan Griggs (vice-chair), Randy Phillips, and Cal Stiles (chair).

Cherokee County faces more than $50 million in costs related to lawsuits over its Department of Social Services practice of separating children from families with an unlawful form to bypass judicial approval.

After merging with The Andrews Journal on January 1, 2019, the Scout has been the only newspaper serving Cherokee County.