It travels from the Florida border near the Quitman area to the South Carolina state line, north of Pollards Corner.

Starting at the Florida line south of Quitman in Brooks County,[2] US 221 heads north concurrent with SR 76.

US 221/SR 76/SR 333 turn east at US 84/SR 38 in front of the Brooks County Probate Courthouse[3] and all five routes stay concurrent until the intersection with Washington Street where SR 76/333 split off to the north.

The routes maintain this name even as they cross the bridge over the Withlacoochee River as well as the Brooks-Lowndes County Line.

All the while, US 84/US 221/SR 38 runs in close proximity to the north side of the same former ACL line it passed over in Downtown Quitman.

After Blanchard Street, the road becomes a divided highway just before crossing a pair of bridges over Knights Creek, then passes by some radio towers for WJEM (1150 AM).

East Park Avenue runs northeast becoming Lakeland Highway, and passes through spares residencies and occasional farm fields of little importance.

The only site of any significance along this route is the Bemiss Auxiliary Army Airfield which is hidden off in a wooden area accessible only by a dirt road just south of the Lowndes-Lanier County Line.

Georgia State Route 135's wrong way concurrency with US 129 ends as soon as it begins, because it is positioned at a pair of T-intersections set close to one another that requires a slight shift to the right for all traffic on North Carter Street.

Despite this, US 221/SR 135 remains a four-lane undivided highway with a continuous left-turn lane and keeps the name Westgreen Road a little longer.

Remaining at the same trajectory, the first community US 221/SR 135 runs through in Jeff Davis County is the small City of Denton.

Northbound US 221/SR 135 makes a right turn onto East Jefferson Street shared by southbound US 23 Business as the beginning of another one-way pair.

[7] US 221/SR 135 crosses the Jeff Davis-Montgomery County Line at the foot of the Neal Lee Gillis Memorial Bridge, a long two-lane causeway over the Altamaha River.

Just after leaving the city limits, the routes are officially named the Edward C. Moses Memorial Highway, continuing to run northwest through rural Montgomery County.

Leaving the square at Railroad Avenue, the routes remain part of downtown Mount Vernon.

The road leaves the city limits along an embankment and culverts over Flat Creek, and after this is named the Gary P. Braddy Highway, and briefly has a second northbound lane.

Further in town, the routes have an intersection with SR 15/SR 29 (West and East Main Streets) just before a railroad crossing.

North of Norristown, the road curves to the north-northeast and remains within that trajectory, even as it passes through the blinker-light intersection with U.S. Route 80.

Further north it curves to the east-northeast where it crosses the Johnson-Jefferson County Line southwest of the intersection with Coleman Chapel Road (Jefferson CR 334).

The road that was previously named Montgomery Street in Johnson County, curves back to the north-northeast and is about to terminate, when US 221/SR 171 is joined by a concurrency with US 319/SR 78.

At the eastern terminus of SR 242 US 221/US 319 officially enters Bartow, the crosses a bridge over the Williamson Swamp Creek.

Continuing along Church Street north of Bartow, US 221/SR 171 stays relatively north as it curves back and forth through western Jefferson County, passing through a few agricultural areas, and residential zones, as well as the occasional church, but mainly forestland with some wetlands hidden in the trees.

The concurrency with SR 171 finally ends at Grange Road, which runs northwest, but US 221/SR 24 crosses another bridge over a tributary to the Ogeechee River before entering Louisville.

curves to the north in front of City Hall, then later joins up with and at-grade interchange with US 1 and SR 4/SR 17 as the business routes for each come to an end.

Just after US 1/SR 4 widens to a four-lane undivided highway, US 221 splits off to the northwest cosigned with SR 47 and passes the Wrens Memorial Airport.

Briefly entering McDuffie County at the bridge over Brier Creek the road encounters only local intersections, and momentarily turns east until it turns northeast again as it passes through Avondale, then later enters Columbia County at a culvert over Boggy Gut Creek, gaining the name Harlem-Wrens Road as well as the additional name of Jake Pollard Highway.

On the northwest corner of the intersection with Clary Cut Road, it passes a water tower and then Harlem High School.

On the north side of this segment, a private road leading from an unfinished intersection is a driveway to the Augusta Sailing Club.