It travels from the Virginia state line near Jenkins to the Ohio state line west of South Shore via Jenkins, Pikeville, Coal Run Village, Prestonsburg, Paintsville, Louisa, Catlettsburg, Ashland, Russell, Flatwoods, Raceland, Wurtland, Greenup, and South Shore.

After a little over a mile (1.6 km), it intersects US 119 at a partial interchange on the Jenkins city line, and US 119 runs concurrently with US 23.

The two then meet US 460 at another partial interchange along the Levisa Fork in extreme southern Pikeville, and US 460 also joins the concurrency.

The highway continues north before curving to the northwest to enter Ashland, where US 60 splits off.

After Greenup, it switches to a more northward direction in parallel with the Ohio River before making a sharp change to the west, after which it enters South Shore.