It was named for the Cherokee people who historically occupied this area prior to European encounter.

In the mid-18th century, waves of British migrants and immigrants, an estimated 250,000 people, traveled by these paths into Cherokee and neighboring counties in the piedmont.

Enslaved African-Americans, for their labor, and as “property,” were the basis of the county's economy until the end of the Civil War.

During the American Revolutionary War, the Battle of Cowpens was fought on January 17, 1781, in northwestern Cherokee County, north of the town of Cowpens, South Carolina, an engagement in the American Revolution's southern theatre resulting in a Patriot victory.

[25] Gaffney Little Theatre and Limestone College serve theater enthusiasts, offering plays and musicals ten to twelve times a year.

Originally constructed in the 1950s, it has had notable early racecar drivers like Bobby Isaac and Curtis Turner compete there.

[26] A major shopping center is Prime Outlets-Gaffney, which attracts almost 3,000,000 visitors per year, and contains over 80 retail outlets.

[27] The area's newest attraction is the Cherokee County History and Arts Museum.

Cherokee County's history, its contributions to the arts, and its role in shaping the culture of the southeast are explored.

[31] As of April 2024[update], Dollar Tree, Limestone University, Nestlé, Timken Company, and Walmart are some of the largest employers in the county.

On March 16, 2006 Duke Power announced that a Cherokee County site had been selected for a potential new nuclear power plant, to be called the William States Lee III Nuclear Generating Station, informally known as Lee Station.

Duke plans to develop the site for two Westinghouse Electric Company AP1000 (advanced passive) pressurized water reactors.

On December 14, 2007 Duke Power submitted a Combined Construction and Operating License to the Nuclear Regulatory Commission, with an announcement that it will spend $160 million in 2008 on the plant with a total cost of 5–6 billion dollars.

[34] In August 2017, Duke Energy announced that construction plans at the site had been put on an indefinite hold.

It carries traffic and trade contributing to the business development along Floyd Baker Blvd, the county's main thoroughfare, which bisects I-85.

A major economic feasibility study is now being conducted, as required for funding by the federal government.

[36] Gaffney is home to several healthcare institutions: Cherokee Medical Center, a division of Spartanburg Regional Healthcare System, is a 125-bed acute care facility located in Gaffney, S.C., that services Cherokee County and the surrounding areas.

[37] The hospital provides services including emergency, medical, surgical and imaging.

One of four locations, Gibbs at Gaffney opened in September 2011 with the mission of providing oncology services to the Cherokee County community.

The local offices include family and internal medicine, cardiology, orthopaedics, hematology oncology, urology and women's care.