The highway connects the Savannah and Millen areas, via Garden City, Port Wentworth, Rincon, Springfield, and Sylvania.

In the city, it used the path of SR 28 (Broad Street) and the Georgia segment of US 25 Bus.

The highway travels to the west-northwest, becoming a freeway, and gains the designation of Interstate 516 (I-516) and the unsigned SR 421.

The highways travel concurrently to the west-northwest, then curve to the north-northeast at the interchange with Veterans Parkway.

After a brief concurrency with US 301/SR 73 Loop around the western side of Sylvania, SR 21 continues west into Jenkins County.

The Tom Triplett Parkway is a section of SR 21 located in Port Wentworth on the west side of the Savannah metropolitan area.

In 2000, the Georgia General Assembly passed a resolution[3] to designate this portion of SR 21 in honor of Tom Triplett,[4] a Democrat who served as Mayor of Port Wentworth and as a State Representative for 18 years.

[5][6] SR 21 was established at least as early as 1919 on its current path from Savannah to Millen, and traveled north-northwest to end in Waynesboro.

A southern bypass of the main part of Augusta was built from US 78/US 278/SR 10/SR 12 on the northeastern edge of Camp Gordon to an interchange with US 25/SR 21 and the northern terminus of SR 56.

[22][23] By June 1963, SR 26 Loop was designated on DeRenne Avenue and proposed to travel west-northwest and then north-northeast to US 17/US 80/SR 17/SR 21/SR 26 just northwest of Savannah.

[23][24] By the beginning of 1966, SR 26 Loop was proposed to be extended from the La Roche Avenue intersection north-northeast to US 80/SR 26 west-northwest of Thunderbolt.

Skidaway Road was established from US 80/SR 26 west-northwest of Thunderbolt south-southwest to DeRenne Avenue.

A western bypass of Sylvania, designated as SR 73 Loop, was proposed from US 301/SR 73 south-southwest of the city to another intersection with those highways north-northwest of it.

SR 121 was extended onto the bypass of downtown Augusta, which was then listed as Gordon Highway.

[24][25] In 1966, SR 26 Loop was extended from Montgomery Street to Liberty Parkway and was under construction from there to Augusta Avenue.

SR 21 was also designated on Skidaway Road from US 80/SR 26 west-northwest of Thunderbolt south-southwest to DeRenne Avenue and continued its previous route.

[48][49] On May 2, 2018, a Lockheed WC-130H transport aircraft of the Puerto Rico Air National Guard crashed and impacted SR 21, near Port Wentworth.

A section of SR 21 at the impact site was closed immediately after the incident, and the Air National Guard has provided funds for repairs and cleanup.

[50] As of May 2018[update], traffic is diverted around the crash site to an adjacent road through a temporary detour, until the Georgia Department of Transportation finishes repairs.

It begins at an intersection with the SR 21 mainline (Augusta Road) in the northeastern part of Garden City, just northwest of the western terminus of Interstate 516 (I-516).

It travels to the northeast and intersects SR 25 (Coastal Road), on the edge of the city limits.

The highway continues to the northeast and reaches its eastern terminus, Georgia Ports Authority's Gate #2, and the entrance to GAF Materials Corporation, on the Savannah River.

It begins on the northeastern edge of Garden City at an intersection with SR 21 (Augusta Road).

After traveling on a bridge over some railroad tracks of Norfolk Southern Railway, it crosses over, but does not have an interchange with, SR 30 (Bonnybridge Road).

Then, it heads to the west-southwest and reaches its northern terminus, an intersection with SR 21/SR 30 (Augusta Road).

[56][57] In May 2017, Savannah and nearby Pooler requested that the Jimmy DeLoach Connector be included into the state highway system.

is a 2.9-mile-long (4.7 km) business route that exists entirely within the central part of Screven County.

The highway passes Screven County Hospital and Brantley Plaza Shopping Center.

[2] In 1937, the path of SR 21 in the southern part of Sylvania had a "completed hard surface".

[66][13] Between the beginning of 1945 and November 1946, the path of the highway in the northern part of the city was hard surfaced.