In 1805, the Creek Nation granted permission to the U.S. government for a horse path to be developed through their territory to help expedite the mail between Washington D.C. and New Orleans. It was known as the Federal Road.

In 1811, the road was widened and it was used for military purposes during the War of 1812 and the Creek War. In 1813, Ferdinand L. Claiborne built Fort Claiborne near the Alabama River to protect the population from attacks by the Northern Creeks, who were conducting a civil war within their nation. The Creek Nation was generally considered one of the five "civilized tribes" and lived peacefully with their white neighbors, frequently there were marriages between persons of the two groups.

The Northern Creeks, who had become known as the Red Sticks, felt that the Lower Creeks were becoming too complacent with the Anglos. They began to conduct raids against white settlers and their Creek and Choctaw neighbors. The U.S. Army, the Lower Tombigbee Militia and friendly members of the Creek and Choctaw conducted raids on the Red Sticks from Fort Claiborne.

In August, 1813, the Red Sticks conducted a massacre at Fort Mims, killing over five-hundred Whites, Creeks and half-bloods, mostly families. This led to a more desperate attitude by the U.S. government, which was already involved in the War of 1812. General Andrew Jackson was then tasked with dealing with the Red Sticks in addition to dealing with the British. The Red Sticks were defeated at the Battle of Horseshoe Bend and the Creek War was over. Fort Claiborne had served its purpose.

In 1816, the settlement of Claiborne was originated on the site of the old fort. At that time, Alabama was part of the Mississippi Territory and was not yet a state.
Located where U.S. Highway 84 crosses the Alabama River are the remains of Claiborne, Alabama. It was situated on a bluff overlooking the Alabama River, near the Federal Road in Monroe County.

Following the Creek War, Claiborne became one of the fastest growing communities in what would, in 1819, become the state of Alabama. Its position on the Alabama River made it a good shipping port and from that, the town grew.
It was surveyed in 1819 and lots were numbered and sold. On December 20, 1820, it was incorporated as a town. It served as the first county seat of Monroe County.

In 1821, the paddle steamer, Harriet, docked at Claiborne. It had navigated farther up the Alabama River than any paddle steamer before. This opened the river port to steam shipping. There were approximately 2,000 residents in Claiborne at the time.

In 1825, the Marquis de Lafayette toured Claiborne and was entertained at the newly constructed Masonic Hall. The town's population at this time was about 2,500.

In time, some very important citizens would leave their footprints in the dirt streets of Claiborne, among them were three Alabama governors, John Gayle, John Murphy and Arthur Bagby. Among them also, was a young lawyer, who in 1836, at the age of twenty-six years, gave his life for the cause of Texas freedom, William Barrett Travis. He was the commander of the Alamo defenders.

In 1832, the county seat was moved from Claiborne to Monroeville, but the town continued to grow. It had two large hotels, a boarding house, various stores, a cotton warehouse, various other businesses, a jail, a school and churches. The population peaked at about 5,000 residents during the 1830s.

In the 1830s, several outbreaks of yellow fever and cholera occurred, having a detrimental effect on population growth. However, it still remained a very important shipping port and business center throughout the 1840s and 1850s.

During the Civil War, the Confederacy installed artillery batteries at Claiborne and other points along the lower Alabama River. The war ended in 1865, as the Battle of Blakeley was being fought to the south. The city of Mobile surrendered. Union troops approached Claiborne and the town was badly looted with little of value left.

Following the war, Claiborne lost significance as a business center and shipping port. The population in the early 1870s was about 350 residents.

In the early twentieth century, a new railroad through Monroe County bypassed Claiborne. In time, with the exception of the Dellet Home and three cemeteries, Claiborne perished.