Florence's founding was an act of geography. In the 1850s the Wilmington and Manchester Railroad and the Northeastern Railroad were both pushing through the eastern Carolinas; their tracks crossed in what was then thinly settled coastal-plain country. A third line, the Cheraw and Darlington, soon connected too. Harllee was president of the Wilmington and Manchester and built his home at the junction, christening the resulting railroad village. The city was chartered in 1871 by the Reconstruction government and incorporated in 1890. Florence County was carved out around it in 1888. Florence's identity as a transportation hub has never really changed - just the modes have. Amtrak's Silver Meteor and Palmetto trains still stop at the Florence station. The Auto Train refuels and changes crews here on its run between Sanford, Florida, and Lorton, Virginia.

During the Civil War the Confederacy built the Florence Stockade just outside town to hold Union prisoners of war evacuated from Andersonville and other Georgia camps. Roughly 18,000 men were imprisoned at Florence; over 2,800 died of disease and exposure and were buried where Florence National Cemetery now stands. The cemetery's marked graves and broader landscape tell that hard story. Florence's twentieth century carried both progress and pain. Marian Wright Edelman - the civil rights lawyer, the first Black woman admitted to the Mississippi bar, the founder of the Children's Defense Fund - was not born in Florence (she was born in Bennettsville), but she is the most famous daughter of the broader Pee Dee. In Florence itself, the modern Civil Rights Center anchored at the McLeod Auditorium tells the local story of segregation, sit-ins, and the slow work of integration. The Florence Museum of Art, Science & History, which opened in 2014, holds the wider collection.

Florence's downtown had emptied out by the 1980s, the way most Southern downtowns did - the malls took the retail, the offices moved to the bypass. In 2010 the city launched a serious revitalization of the seventy-block central district. The Drs. Bruce and Lee Foundation Library, an 18-million-dollar anchor, was the first big move. The Francis Marion University Performing Arts Center opened in 2011. The Florence Museum of Art, Science & History opened October 11, 2014. The new Florence Little Theater opened in 2008, replacing the 1968 building, and in 2023 the theater celebrated its hundredth season opening with The Sound of Music - the original Community Players had formed back in 1923. Evans Street, the main central commercial corridor, has been streetscaped block by block. Apartments returned to upper floors. The work is not finished, but Florence's downtown is no longer a place people only drive through.

Florence's economy works because its location works. The intersection of I-95 (which runs from Maine to Miami) and I-20 (which runs from Florence to Texas) sits about halfway between New York and Miami. That has attracted distribution centers and regional headquarters: QVC's distribution operation, Honda manufacturing, General Electric, Otis Elevator, AT&T, Duke Energy's southeastern headquarters, CSX, Wells Fargo, Truist. McLeod Regional Medical Center, a 517-bed nonprofit on a 75-acre downtown campus, anchors the regional healthcare economy and is the largest employer in the Pee Dee. The Medical University of South Carolina took over the former Carolinas Hospital System as MUSC Florence in recent years. Together they employ thousands in a city of forty thousand. Florence Regional Airport (ICAO KFLO) handles American Eagle service to Charlotte. The city is the second-busiest aviation gateway in the region after Myrtle Beach International (KMYR), about seventy miles east.

Florence has produced an unusual range of public figures. Cale Yarborough, NASCAR's four-time Daytona 500 champion, came up here. Buddy Baker, another Daytona 500 winner, was a Florence boy. Harry Carson, the New York Giants linebacker and Hall of Famer, came out of Florence. Reggie Sanders played his minor-league ball at Florence on his way to a long major-league career. The artist William Johnson, born in Florence in 1901, became one of the most important American modernist painters of the Harlem Renaissance era. Henry Timrod, the so-called poet laureate of the Confederacy, lived and died here; complicated history again. Padgett Powell, the novelist. Gillian Murphy, the ballet dancer. Mark L. Walberg, the television host. The Florence Flamingos play summer-collegiate baseball at Sparrow Stadium. The Florence Civic Center hosts the conferences. Old Florence, new Florence, both keep going.