Driving around Zanesville, Ohio

Zanesville was named after Ebenezer Zane (1747–1811), who had blazed Zane's Trace, a pioneer trail from Wheeling, Virginia (now in West Virginia) to Maysville, Kentucky through present-day Ohio. In 1797, he remitted land as payment to his son-in-law, John McIntire (1759–1815), at the point where Zane's Trace met the Muskingum River. With the assistance of Zane, McIntire platted the town, opened an inn and ferry by 1799. In 1801, Zanesville was officially renamed, formerly Westbourne, the chosen name for the settlement by Zane.

From 1810 to 1812, the city was the second state capital of Ohio. The National Road courses through Zanesville as U.S. Route 40. The city grew quickly in the 1820s–1850s. The city and the city of Putnam (eastern side of Muskingum River) from the 1840s until the Civil War broke out was part of the 'Underground Railroad'. In excess of 5,000 Union soldiers, along with hundreds of townsfolk, were stationed in the Zanesville area to protect the city in 1863 during Morgan's Raid. Novelist Zane Grey, a descendant of the Zane family, was born in the city.

"Lorena" was a popular campfire song on both sides during the American Civil War. The song was based on an ill-advised love affair that took place in Zanesville in the late 1850s. The song has been sung in many Westerns and Civil War movies as well. John Ford used the song as background in many of his movies. Today, a sight-seeing sternwheeler named Lorena (summer/fall) cruises on the Muskingum River.

In 1872, Zanesville annexed the adjacent community of Putnam. It is now the Putnam Historic District of Zanesville.

The city was historically known as a center for pottery manufacturing; in the first half of the 20th century, more than a dozen potteries operated in the city and the surrounding areas. Bolstered by ample local clay deposits and rivers, the area produced both art pottery and functional, utilitarian pottery. Notable pottery manufacturers that operated in the area included the S.A. Weller Pottery Company, J. B. Owens Pottery Company, Roseville Pottery Company, American Encaustic Tiling Company, and the Mosaic Tile Company. The city peaked economically in the 1950s, and like many cities experienced a post-industrial decline. The city today has a relatively high level of chronic poverty and unemployment and a relatively low level of labor force participation and educational attainment.

In 2016, the Good Samaritan campus (hospital) and the Bethesda campus merged to form the enlarged Genesis hospital, located on Maple Avenue (Ohio Route 60); the Good Samaritan campus, located on Forest Avenue, was closed and demolished.

The city has two engineering landmarks: the Muskingum River Canal, designated a National Historic Civil Engineering Landmark; and the Zanesville Y-Bridge, the only such structure in the United States in operation. It is listed on the National Register of Historic Places.