KY 181 starts at a crossroads junction with U.S. Route 79 and Kentucky Route 2128 located near the Tennessee state line in the town of Guthrie, in southern Todd County.

It intersects US 68 Business at the Todd County Courthouse in downtown Elkton.

At Tyewhopperty, it intersects KY 1785 shortly before entering Muhlenberg County.

[5][6] After making its entrance into Muhlenberg County, KY 181 has a junction with Kentucky Route 973, which provides access to the Lake Malone State Park.

In downtown Greenville, it meets U.S. Route 62 (US 62) and KY 176 at the town square.