SR 22 originally traveled only from Columbus to Macon, and was incrementally extended to Comer in stages.

The part of the highway from the Alabama state line east to Geneva is part of the Fall Line Freeway (SR 540), a long-distance four-lane highway that extends from Columbus to Augusta.

Almost immediately into Georgia, the road has an interchange with the northern terminus of SR 22 Conn. (2nd Avenue).

The highway then parallels the northern border of Fort Moore and travels through the community of Upatoi, still inside the Columbus city limits.

The road then crosses Baker Creek into Talbot County, traveling just north of the community of Box Springs and later meeting the northern terminus of SR 355.

A few blocks later, SR 41 also leaves the concurrency to the north on Washington Avenue, while US 80/SR 22 curves east.

Not long afterward, US 80/SR 22 splits off to resume an eastern course, shortly entering Crawford County.

In nearby Knoxville, SR 42 departs the concurrency, while US 80/SR 22 curves east-northeast into the rural eastern part of Crawford County.

The highway then crosses Echeconnee Creek into Bibb County and the community of Lizella, widening to a four-lane divided highway shortly before entering the city of Macon and taking on the name Eisenhower Parkway.

Then, they pass Saints Rest Cemetery and Memorial Park, before they intersect US 41 Bus./US 129/SR 11/SR 49 (Broadway).

On the southwestern edge of the city limits of Gray, SR 18 joins the concurrency.

departs to the south-southeast on North Clark Street, concurrent with SR 29 Bus.

SR 22/SR 24 parallel the northern edge of Georgia College & State University.

At this intersection, SR 22/SR 24 turn to the left onto East Hancock Street and leave town by crossing over the Oconee River.

The two highways diverge with SR 22 heading to the northeast and entering Hancock County.

Almost immediately, they curve to the north-northeast and split, with SR 15/SR 22 continuing straight ahead.

After a curve back to the north-northwest, SR 22 splits to the northeast and travels through Powelton.

After an interchange with I-20 (Carl Sanders Highway), it enters Crawfordville, where it intersects US 278/SR 12 (Broad Street).

It parallels the southwestern edge of A. H. Stephens Historic Park and leaves town.

The concurrency crosses the southeasternmost corner of the city limits on Main Street.

On the northwesternmost corner of the city limits, SR 22 splits off to the northeast on Comer Road.

The highway crosses over the South Fork Broad River into Madison County.

[24][25] Between June 1963 and the beginning of 1966, the path of US 80 from the central part of Columbus to northeast of the city was shifted northward, off of SR 22 and onto US 27/SR 1/SR 85/SR 103 and then US 27 Alt./SR 85.

[26][27] In 1967, the path of US 80 from the Alabama state line to 4th Avenue was shifted southward, off of SR 22 and onto US 280/SR 1 Spur and US 27/SR 1.

The former path from 4th Avenue to the northeast was redesignated as a southwestern extension of SR 22 Spur.

The former path from the Alabama state line to 4th Avenue was redesignated as part of SR 85/SR 219.

It travels due north, curves to the north-northeast, and meets its northern terminus, an interchange with US 80/SR 22/SR 540 (J.R. Allen Parkway/Fall Line Freeway).

Then, it takes on the name Macon Road and has an interchange with Interstate 185 (I-185; Lindsay Creek Bypass).

Just after traveling northwest of Fort Moore, it meets its eastern terminus, an intersection with US 80/SR 22/SR 540 (Beaver Run Road/Fall Line Freeway).

[26][27] In 1983, the western terminus of the SR 22 mainline was truncated to the US 27 Alt./US 80/SR 1/SR 85 interchange northeast of downtown.