The John Day Highway begins at an interchange with Interstate 84, one mile (1.6 km) north of Arlington.

It follows OR 19 southward for about 76 miles (122 km), through the cities of Condon and Fossil, where it meets with OR 207 at Service Creek.

Here the highway turns eastward and follows OR 207 for 16 miles (26 km) to Spray.

The highway passes the community of Kimberly, through the John Day Fossil Beds National Monument, and meets up with U.S. 26.

The highway then follows US 26 eastward, through the communities of Dayville, Mount Vernon, Prairie City, Unity, Ironside, and Jamieson.