The highway heads northeast, crosses and intersects with Interstate 5, and continues east along the northern edge of the Siskiyou Mountains.

Six miles east of Ashland, the highway intersects with Oregon Route 273, near the Klamath Falls Junction.

The highway ends at an interchange with U.S. Route 97 in Klamath Falls; just west of this interchange the highway intersects and briefly overlaps Oregon Route 140.

OR 140 continues east of the US 97 interchange, past the Klamath Falls airport, and eventually towards Lakeview.

At that time, OR 66 west of Klamath Falls Junction (and OR 273 south of there) was U.S. Route 99; in 1938 a new route over Siskiyou Pass was completed, and the highway assumed its current configuration.