Early settlers of Middleton are said to have migrated to the area from small settlement of Slab Town, located approximately three miles north of Old Stateline Road at Sandy Springs, on an old stage coach line that ran between Memphis and Corinth. For years Middleton was widely known as the Jenkins-McCommons Crossing, named for William Taylor (Zack) McCommons and Jese Jenkins, who came to Middleton from North Carolina in 1849, and donated much of the land on which Middleton was founded. In 1850, following the extension of the Memphis and Charleston Railroad and construction of the depot, the town was chartered and officially named Middleton in honor of a "distinguished Memphis and Charleston official".
Civil War - Middleton, like most Hardeman County towns, was devastated by the Civil War. An old log structure that served as the town's first store, was the only business left standing after the war. It stood on the site now occupied by the Liberty Baptist Church. The oldest existing structure is Rose House on North Main Street, built by Benjamin Rose after 1833. The Methodist Church/Adams Masonic Lodge #264, bilt in 1859, still stands on the edge of the town square.