Throughout the second half of the 18th century, starting with Christopher Gist in 1750, American colonists explored the area as the Ohio Company surveyed.

George Washington, while engaged in land examinations, camped in the area of present-day East Liverpool in October 1770.

[5] In the 1780s, the Native Americans relinquished control of the area, and the region was surveyed in accordance with the Land Ordinance of 1785.

The ensuing Public Land Survey System of the United States started by surveyor Thomas Hutchins on north bank of the Ohio River in present-day East Liverpool resulted in the Seven Ranges, believed to be "the first mathematically designed system and nationally conducted cadastral survey in any modern country.

"[6] The first permanent settlement in the area was in 1792 or 1793, by hunter John Quinn, who settled near present-day Calcutta in St. Clair Township.

[5] Columbiana County was founded in 1803 and named in honor of Christopher Columbus, combining his surname with the suffix -iana.

[5] The county was the scene of one of the northernmost action fought during the American Civil War; on July 26, 1863, Confederate raiders under John Morgan were surrounded and captured by Union forces at the Battle of Salineville.

The county was home to the largest pottery industry in the world, in East Liverpool & surrounding communities, which produced more than half of the United States' annual ceramics output.

[7][8] Other chief industries included iron and brick making, as well as transportation via the Ohio River, Sandy and Beaver Canal, and Pennsylvania Railroad system.

[5] On February 3, 2023, a freight train containing hazardous materials including vinyl chloride derailed in East Palestine.

In only eight elections from 1856 to the present has a Democratic Party candidate won the county, the most recent being Bill Clinton in 1996.

This trend was most apparent in 2016 when Donald Trump posted the best showing by a Republican in the county since Herbert Hoover in 1928 with a 41.4-point margin of victory over Hillary Clinton.