The history of Florence County is much the history of Marion County until it split off in 1888, with the city of Florence as its county seat.

Henry Timrod lived on the plantation of Colonel William Henry Cannon, who constructed a school for Timrod to teach the plantation children in 1856 and 1857. This school is located in Timrod Park in Florence today. Three railroads were constructed in the Pee Dee. All intersect in what is known today as Florence.

Florence began as a railroad depot and an inn. The town started as a plot of 577 acres as a grant from the state. In 1859 Jerome P. Chase, a telegraph operator arrived and became a successful businessman, selling insurance and real estate and he became known as the "Father of Florence." The town was named for his daughter, Florence. In 1860 the first map of Florence was created. Florence was a planned community with seven streets and ninety-six lots.

After the US Civil War, the Northeastern Railroad was the primary employer, and the town grew around the transport of agricultural products from the surrounding Pee Dee River Basin.

In 1888, the South Carolina General Assembly created the "County of Florence," encompassing the towns of Timmonsville, Coward, and Lake City with the town of Florence as its county seat. Two years later, the City of Florence was incorporated.