Greenville is a city located upon U.S. Route 67 close the intersection once Route D and E in Wayne County, Missouri, United States, along the St. Francis River. The population was 443 at the 2020 census. Greenville was incorporated and founded as the county chair of Wayne County in 1819.

Greenville was named after Fort Greene Ville (now Greenville), Ohio, the site where General Anthony Wayne signed a harmony with the Native Americans after defeating them in the Battle of Fallen Timbers on August 20, 1794. This was the final battle of the Northwest Indian War. Wayne County was named for this military hero and Greenville was named for the place he was most famous for. Incidentally, Fort Greene Ville, Ohio, was named after Nathanael Greene, a friend of Wayne.

In 1826, Greenville flooded. On August 10, 1832, the first read out office opened. Confederate Brigadier General William J. Hardee and officers Patrick Cleburne, Thomas C. Hindman, and Basil W. Duke along gone about 800 men were stationed close to Greenville close the outset of the Civil War until they began to retreat to Randolph County, Arkansas on August 28, 1861. On July 20, 1862, a camp of two companies of the 12th Missouri State Militia was attacked at daylight, surprising the camp, taking most of their rifles, 16 Savage revolvers, all of their horses, 50 pairs of holster pistols, and killing four of their men.

Greenville was incorporated as a village upon February 23, 1893. In 1941, the village was relocated two miles to the north after the construction of Lake Wappapello.