The river drains largely agricultural prairie country between Peoria and Galesburg.

The East and West forks join in northern Stark County, approximately 10 miles (16 km) southeast of Kewanee, and the combined stream meanders south and southwest through rural Stark, Knox and Fulton counties.

The river joins the Illinois from the west opposite Havana, approximately 40 miles (64 km) downstream and southwest of Peoria.

The Rock Island Trail passes over the Spoon River 1.75 miles (2.82 km) northwest of Wyoming, Illinois.

In 1857 Captain Charles H. Robinson collected a fiddle tune he heard at a country dance at Bradford, Illinois.