[4] In its heyday, notable industries in Wellsville included shipping via the Ohio River and Pennsylvania Railroad, as well as pottery and ceramics manufacturing.

In 1770, George Washington with his friend and personal surveyor, William Crawford, embarked on a journey down the Ohio River from Pittsburgh for the purpose of viewing lands to be apportioned among soldiers who had served in the French and Indian War.

They are reported to have surveyed the Wellsville area, just north of Yellow Creek in 1770,[5] and it was noted in his journal that it was good bottom land.

A group of Virginian settlers killed the relatives of a prominent Iroquois leader, Logan, who was camped on Yellow Creek.

Wellsville was founded in 1797 by William Wells, a Pennsylvanian, and former justice of the Territory Northwest of the River Ohio.

A barn built in 1807 by the Aten family was moved to Hale Farm and Village in Bath, Ohio.

[7] In 1814, a turnpike road was built to Lisbon, and in 1816, a post office was established with John J. Feehan serving as postmaster.

Wellsville finally took shape around 1823, when William Wells recorded that lots had been laid out for planned settlement.

On February 14, 1861, Abraham Lincoln, on his way to his first inauguration, spoke to a large gathering in front of the Whitacre House, a hotel, in Wellsville.

[10] On July 26, 1863, Confederate States Army General John Hunt Morgan and several hundred of his soldiers surrendered to pursuing Union forces after Morgan's Raid ended in nearby West Point, and were held in Wellsville before being shipped to the Ohio Penitentiary in Columbus.

At this time, Ohio State Route 45 was known as the Warren-Ashtabula Turnpike, which ran from Wellsville to Lake Erie.

During the 1896 presidential campaign, Democratic candidate William Jennings Bryan addressed a crowd in Wellsville from the back of a train.

Bryan was the first candidate to successfully embrace "whistle stop" campaigning, harnessing the power of a young rail network to reach masses of voters.

[citation needed] In 1986, the 1870 Episcopal Church of the Ascension and Manse was listed on the National Register of Historic Places.

Wellsville operates under a council–manager government, where there are six council members elected as a legislature in addition to the mayor, who serves as an executive.

As of 2025, the mayor is Robert Boley (D), the village administrator is Jarrod Grimm, and the fiscal officer is Hoi Wah.