Vonore's location at the confluence of the Little Tennessee River and the Tellico River places it near the center of one of the richest archaeological regions in the southeastern United States. The Icehouse Bottom site, located near Fort Loudoun, was occupied by Native Americans as early as 7500 B.C., making it one of the earliest known semi-permanent habitation sites in Tennessee. Icehouse Bottom and nearby Rose Island were occupied for extensive periods during the Woodland period (c. 1000 B.C. - 1000 A.D.). They were part of a vast trade network that stretched from Ohio to Florida. A substantial Mississippian period (c. 1000-1600 A.D.) village was located at Toqua, immediately south of Vonore. There is some evidence that Toqua's Mississippian village was the village of Tali, visited and recorded by the Hernando de Soto expedition in 1540.
By the time Euro-American explorers arrived in the area in the 18th century, the Overhill Cherokee had established several villages along the Little Tennessee. These villages included Tanasi, the namesake for the state of Tennessee, and Chota, the capital and most prominent Cherokee village in the 18th century. Mialoquo, the home of the Cherokee chief Dragging Canoe, was located just north of the modern US-411 bridge. Tuskegee was located just south of the future Fort Loudoun. It was the birthplace of Sequoyah, creator of the written Cherokee syllabary.
Fort Loudoun was an English colonial fort built in 1756 in hopes of obtaining Cherokee assistance in the French and Indian War. The Tellico Blockhouse, an American outpost located across the river from Fort Loudoun, was built in 1794 to help keep the peace between the Cherokee and the fast-encroaching American settlers.
In 1819, the Cherokee signed the Calhoun Treaty, relinquishing what is now Monroe County to the United States. The county itself was established shortly thereafter. In 1890, the Atlanta, Knoxville and Northern Railroad laid tracks through Monroe County. A stopover known as Upton Station was established just beyond the railroad's Little Tennessee River crossing. Three years later, an area doctor named Walter Kennedy applied for a post office for Upton Station. When the postal service informed him that Upton Station had been taken, Kennedy chose the name "Vonore", a combination of the German word von (meaning "of") and the English word "ore", as Kennedy believed the town would become a mining town.
Most of the valley's archaeological sites were flooded in 1979 when the Tennessee Valley Authority completed Tellico Dam at the mouth of the Little Tennessee. Preservationists aided by Works Progress Administration (WPA) funds had reconstructed Fort Loudoun in the 1930s. Additional reconstruction was undertaken in the 1970s and 1980s, including moving the fort out of range of water which the dam would raise. After archaeological excavators located the foundation of the Tellico Blockhouse in the 1970s, they placed posts and fill to give visitors an idea of its layout. Both are now part of Fort Loudoun State Park.