Florence is the merger point for two major U.S. Highways, as well as several Alabama Highways. Both U.S. Highway 43 and U.S. Highway 72 merge just east of the city limits in Killen, and are co-signed their entire length through the city.
Highway 43, running north and south, helps connect the city to Lawrenceburg and Columbia to the north in Tennessee, as well as Tuscaloosa and Mobile to the south. Highway 72 helps connect the city to Huntsville and Chattanooga, Tennessee to the east and Memphis, Tennessee to the west.
Interstate 65 is accessible about forty-five minutes east on Highway 72. Both of these roads cross the Tenneessee River on O’Neal Bridge, connecting Florence to Sheffield.