After crossing the East Bay portion of Apalachicola Bay via the John Gorrie Bridge, US 319 runs along the Gulf coast of Florida's Panhandle to Carabelle in Franklin County, and departs the coast, and its concurrency with US 98, about halfway between Carrabelle and Bald Point State Park, in a north direction through Sopchoppy in Wakulla County.

In Sopchoppy, the route angles east, briefly meets up with US 98 once more, before parting ways again and running north through Crawfordville, where it receives the FDOT maintenance designation of State Road 369, into Tallahassee in Leon County.

US 319 again becomes a 4-lane divided highway at its intersection with County Road 0342 about 9 miles (14 km) from I-10, and runs to the state line with Georgia.

US 319 then continues northeast, passes through Coolidge, and crosses into Colquitt County, running as a bypass around the east of Moultrie.

The following portions of US 319 and SR 35 are part of the National Highway System, a system of routes determined to be the most important for the nation's economy, mobility, and defense: The entire length of US 319 in Franklin County was designated as "Blue Star Memorial Highway" by the Florida State Legislature in 1957.

[6] The section of US 319 that is co-signed with US 98 and SR 30 in Medart in Wakulla County was designated as "Agnes Morrison Memorial Highway" by the Florida State Legislature in 1961.

[6] US 319 does not make an appearance on Georgia road maps until October 1937, when the spur from the Florida state line to Thomasville is shown, co-signed with SR 3.

[11] The section of US 319 that forms the east bypass around Moultrie in Colquitt County was designated as "Veterans Parkway" in 2002.

begins at an intersection with US 319/SR 35 (Veterans Parkway) and SR 33 (Pavo Road) in the south-central part of Moultrie.

and SR 33 travel concurrently as South Main Street to the north-northwest and immediately curve to the north-northeast.

Just past an intersection with the eastern terminus of Hugh Bannister Drive, they begin a curve back to the north-northwest.

Just south of an intersection with the northern terminus of Lower Meigs Road, the highways curve back to the north-northeast.

On the southeastern corner of the intersection with 2nd Avenue SE lies the main office for Southwest Georgia Bank.

Just north of 9th Avenue NE, they travel on a bridge over some railroad tracks of Norfolk Southern Railway (NS).

Just south of Sylvester Drive, the southbound lanes have an intersection with SR 111 (West Bypass NW).