The highway, situated around several oil wells, progresses to the northwest through a moderately populated region of residential homes.

After an intersection with a local dirt road, the highway leaves Ormsby and continues into the under-populated forests in Keating Township.

When PA 646 turns to the north at a gradual bend, it crosses a second pipeline and enters the community of Cyclone.

[3] Upon entering Cyclone, PA 646 intersects with Pithole Road, which heads to the northeast and into McQuen Hollow, a local mountain range.

After an intersection with Boyland Road, the highway turns to the north and leaves Cyclone for the woodlands in Keating Township once again.

The route continues northbound for a couple miles, entering the community of Gifford, situated near the Lafayette Township line.

PA 646 continues, making an intersection with Wolf Run Road, which heads southward to the community of Middletown.

The highway continues northward, winding around several mountains through the Bradford Oil Field, passing a large swamp before entering the small community of Summit.

In Red Rock, most of the highway is unpopulated, until an intersection with Narrow Gauge Road, where most of the residential homes stand.

In Derrick City, the highways pass along a stretch of residential houses before PA 646 turns off to the north on Olean Road.

When the route turns to the east, PA 646 intersects with a connector street back to Bells Camp Road, which parallels to the north.

The route continues northward, paralleling PA 546 and Knapp Creek, before crossing the state line into New York a distance northwest of Fullerton.

The first one is 32.15 feet (9.80 m) long, and is a concrete tee beam bridge that handles an average of 957 people daily (2004).

[11] The final bridge along PA 646 was constructed 1 mile (1.6 km) north of Gilmore over Pennbrook Run.