[1] It drains a rugged area of the Allegheny Plateau in the Ohio River watershed, flowing through narrow serpentine valleys and hardwood forests.

The river flows generally west-southwest across western Pennsylvania in a tight meandering course past Ridgway and Clarion.

It joins the Allegheny from the east in western Clarion County approximately 5 mi (8 km) south of Emlenton.

Before 1817, the Clarion River was more commonly called "Tobeco," likely a corruption of Tuppeek-hanne, meaning the stream that flows from a large spring.

This deforestation significantly degraded the watershed of the upper Allegheny in general, leading to floods downstream (particularly in Pittsburgh), and eventually to the declaration of the national forest in 1923, but in the case of the Clarion River, run-off from tanneries compounded the problem, as did acid mine drainage.