Many wealthy planters settled in the area, leaving a legacy of historic mid-19th-century architecture that largely survived intact into the modern era.

A brief skirmish was fought at Lowndesboro in April 1865 between a group of Confederate cavalry and advance troops of the Union Army during Wilson's Raid.

Federal troops occupied the town after driving off the Confederate force, with very little destruction noted from the occupation, thus preserving many of the antebellum houses and structures in the Lowndesboro Historic District.

[6] Like many small Southern communities with an economy based on cotton production and trade, Lowndesboro declined rapidly in the post-war years.

On March 25, 1965, civil rights worker Viola Liuzzo was shot to death during a high-speed chase by Ku Klux Klan members on U.S. Route 80, while driving to Montgomery to pick up a group of demonstrators waiting to return to Selma after the Selma-to-Montgomery march.

The Klansmen spotted the white Liuzzo and her black passenger, Leroy Moton, at a stoplight in Selma, catching up to the pair about two miles (3 km) west of Lowndesboro.

[9] In 1966, a number of Lowndes County African-American families were evicted from their homes in retaliation for their participation in the movement.

In 1880, it was the largest town in the county with 472 residents, ahead of Fort Deposit (350) and White Hall (168), the only two other communities separately returned.