It begins in Carter County at State Route 67 and ends in Johnson County at the North Carolina state line.

SR 159, overlain by US 321, traverses 12.5 miles (20.1 km) along the banks of Watauga Lake.

In 2011–12, a bridge replacement project closed a section of the highway at the Elk River; a detour route was signed using both US 321 and SR 159, along SR 67 and US 421 in Tennessee to Vilas, North Carolina, where it ended.

This was the only time SR 159 has ever been signed during its entire existence.

[2][3] State Route 159 traverses the counties shown in the table below.