Knoxville is in south-central Iowa, 35 miles southeast of Des Moines.

The area was originally inhabited by Native Americans of the Sac and Meskwaki tribes.

In 1842, the Sac and Fox Indians signed a treaty to sell lands in central Iowa to the new settlers known as the New Purchase of 1842.

They named Knoxville in honor of General Henry Knox, hero of the Revolutionary War.

Powers platted part of the town in September 1845, shortly after it was founded.

Knoxville remained an unincorporated village until 1853, when a movement for incorporation began.

In early 1853, the citizens of Marion County created a committee to attract railroad development to the county and to Knoxville, promising to buy shares in any railroad that reached town.

The first contender was the Muscatine, Oskaloosa & Council Bluffs, proposing an east–west line that would pass through Knoxville, the line being suggested in January 1868 by the proposed Muscatine, Oskaloosa & Council Bluffs.

[5] By 1875, when this line reached Knoxville, it was the Chicago, Burlington & Quincy Railroad.

The second railroad to reach Knoxville was the Chicago, Rock Island & Pacific, which completed a line from Oskaloosa in 1876.

For several years, the Number 5 mine in Flagler was one of Iowa's most productive, employing around 150 men and working a coal vein over 8 feet (2.5 m) thick.

Shortly after the railroad reached Knoxville, J. T. James opened a coal mine in town eight blocks north of the courthouse.

In the 1880s, the White Breast Fuel Company opened the Number 11 mine at Flagler.

The mine continued operating until 1892, working in progressively thinner coal as it expanded.

Knoxville is 2 miles (3.2 km) east of White Breast Creek and 6 miles southwest of the confluence of White Breast Creek and the Des Moines River in Lake Red Rock.

According to the United States Census Bureau, the city has an area of 4.63 square miles (11.99 km2), all land.