Despite extensive historical data on the Mobile, there is little prehistoric information. In 1540, Hernando de Soto first fought with the Mobile, who were under the leadership of their chief, Tuscaloosa, who rallied his people and neighboring groups to oppose the Spanish successfully.

Later, many Mobile moved south to Mobile Bay, where the French encountered them in 1700. The Mobile appealed to the French for protection from their traditional enemies, and in 1708 they were settled near Fort Louis, along with the Tohome. French Roman Catholic missionaries were relatively successful in Christianizing the Mobile, who were absorbed into the Choctaw Nation. By 1758 there remained fewer than two hundred Mobile.

In addition to their own language, the Mobile spoke a so-called Mobilian lingua franca, or trade language, which actually was a corrupted Choctaw jargon used by most tribes from Florida to Louisiana, and north along the Mississippi.