The Memphis area was first settled by the Chickasaw tribe. European exploration came years later, with Spanish explorer, Hernando de Soto believed to have visited what is now the Memphis area as early as the 1540s. By the 1680s, French explorers led by René Robert Cavelier, Sieur de La Salle built Fort Prudhomme in the vicinity, the first European settlement in what would become Memphis, predating English settlements in East Tennessee by more than 70 years.

Despite such early outposts, the land comprising present-day Memphis remained in a largely unorganized territory throughout most of the 18th century, while the boundaries of what would become Tennessee continued to evolve from its parent — the Carolina Colony, later North Carolina and South Carolina. By 1796, the community was the westernmost point of the newly admitted state of Tennessee.

Memphis was founded in 1819 and incorporated as a city in 1826, taking its name from the ancient capital of Egypt. At the conclusion of the Battle of Memphis on June 6, 1862 during the American Civil War, Union forces captured Memphis from Confederate control. Yellow fever epidemics in the 1870s (1873,1878,1879) devastated the population for many years thereafter. As a result, in 1879, Memphis lost its city charter, and until 1893, was a Nashville taxing district. In 1897, Memphis' pyramid-shaped pavilion was a conspicuous part of the Tennessee Centennial exposition. From the 1910s to the 1950s, Memphis was a hotbed of machine politics under the direction of E. H. "Boss" Crump. The city was at the center of civil rights issues during the 1960's, notably as the location of a sanitation workers' strike. Memphis is also known as the place where Dr. Martin Luther King, Jr. was assassinated on April 4, 1968 at the Lorraine Motel.

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