Tuscumbia was the hometown of Helen Keller, who lived at Ivy Green.

When the Michael Dixon family arrived about 1816, they were the first European Americans to settle here.

The settlers traded with Chief Tucumseh for the Tuscumbia Valley and built their home at the head of the big spring.

Other settlers joined them and there developed a village known as the Big Spring Community.

The men of the community requested that the state legislature incorporate them as a city.

[9] The town was incorporated in 1820 as Ococoposa, a Chickasaw word meaning 'dry watermelon'.

In 1821, its name was changed to Big Spring[10] and on December 22, 1822, to Tuscumbia, after the Chief Rainmaker of the Chickasaw.

[13] It was one of a number of private schools[citation needed] founded by planters and others wealthy enough to pay for the education of their sons and daughters.

The Civil War resulted in the permanent closure of the Tuscumbia Female Academy.

[15] A tornado, estimated at F4 intensity on the Fujita scale, struck Tuscumbia on November 22, 1874, damaging or destroying about a third of the town and killing 14 people.

[16] In April 1894, three African Americans accused of planning to commit arson were taken from the Tuscumbia jail by a mob of 200 men and lynched, hanged from the bridge over the Tennessee River.

The 2019–20 coronavirus pandemic resulted in the temporary closure of two tourist destinations: The Alabama Music Hall of Fame and Ivy Green at the beginning of the month of April 2020 to reduce social contact and help curb the spread of COVID-19.

34.5% of all households were made up of individuals, and 17.5% had someone living alone who was 65 years of age or older.