The river's course is generally southeast through the counties of Nemaha, Brown, Jackson, Atchison, and Jefferson in northeast Kansas.

Just south of Valley Falls the river enters Perry Lake, a man made reservoir to control flooding.

Some cities within 10 miles (16 km) of the river include, Sabetha, Fairview, Powhattan, Horton, Whiting, Muscotah, Holton, Valley Falls, Ozawkie, Perry, and Lecompton, Kansas.

In Valley Falls it is crossed by the Delaware River Composite Truss Bridge, built in 1936, which is listed on the National Register of Historic Places.

[5] The river forms Perry Reservoir, which is a major regional lake for boating, swimming, camping, fishing and other activities.