The following portions of US 341 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: US 341 begins at an intersection with US 17 and SR 25 (Glynn Avenue) in the southeast corner of the city of Brunswick, a short distance north of the Sidney Lanier Bridge.

The highway turns north onto Newcastle Street and passes along the edge of the Port of Brunswick.

[5][1] US 25/US 341/SR 27 continues north along Newcastle Street as a four-lane highway with center turn lane out of the city of Brunswick.

The three highways enter the city as Cherry Street between their crossing of Penholoway Creek and their intersection with US 301/SR 23; US 25 splits north to join US 301/SR 23 toward Ludowici.

The highway intersects SR 121 (Still Street) in the town of Surrency and crosses Satilla Creek.

The two highways enter along Jarman Street and intersects and travels concurrently with US 23/US 221 Truck/SR 19/SR 135 Truck.

Near the center of town, the six highways meet the northbound lanes of US 221/SR 135 (Cromartie Street).

US 341/SR 27 becomes Eastman Highway and crosses Mosquito Creek as it enters Pulaski County and approaches the city of Hawkinsville.

The south leg of the intersection is Lower River Road, which carries SR 230.

US 341/SR 11 has an acute intersection with SR 127 (Houston Lake Road), with which the highways travel concurrently for five blocks.

[5][1] Northwest of Perry, US 341/SR 7 reduces to two lanes and closely parallels a Norfolk Southern rail line into Peach County.

The highways enter the city of Fort Valley as Martin Luther King Jr. Drive.

Just east of downtown, US 341/SR 7 turns onto Oakland Heights Parkway, which crosses over a second Norfolk Southern rail line before meeting and becoming concurrent with SR 96 at an acute intersection.

US 341/SR 7 intersects SR 49 Conn./SR 540 (Fall Line Freeway) as it leaves Fort Valley shortly before entering Crawford County.

The highways enter the town of Roberta along Dugger Avenue, which meets the eastern terminus of SR 128 (Agency Street).

At the same intersection, US 341/SR 7 becomes concurrent with SR 42, which follows US 80/SR 22 east to the adjacent community of Knoxville.

US 341/SR 7 continues northwest into Lamar County and reaches its northern terminus at a three-legged intersection with US 41 and SR 18 on the southeastern edge of Barnesville.

In March 2018, the Georgia Department of Transportation petitioned AASHTO to eliminate US 341 Byp.