The route travels eastward across the bootheel, and it goes through the towns of Arbyrd, Hornersville, Rives, and Steele.

It becomes concurrent with US 61 briefly in Steele, and intersects Interstate 55 (I-55) east of the city.

The route ends east of Cottonwood Point, near the Mississippi River.

In 2015, Missouri Department of Transportation (MoDOT) calculated as many as 2,454 vehicles traveling on Route 164 west of I-55, and as few as 482 vehicles traveling east of Route H. This is expressed in terms of annual average daily traffic (AADT), a measure of traffic volume for any average day of the year.

Route 164 travels eastward and leaves Cardwell past County Road 613 (CRD 613).

The road turns northeastward and parallels Little River until it reaches the unincorporated area of Cotton Plant.

The road intersects Route TT, southwest of the village of Rives.

It soon meets the terminus of Route PP, which leads to the center of the village, less than one mile later.

[3] At Administration Drive, the road enters the city limits of Steele.

[1] Around 1933, Route Y was designated along a gravel road from Cardwell to Caruth, through the community of Hollywood.