Eastern cottonwood seedlings and young trees are browsed upon by a variety of mammals including rabbits, deer, and domestic livestock. Beavers are known to use cottonwood poles for construction of their dams.

The poplar petiole gall aphid (Pemphigus populitransversus) lays its eggs on cottonwood leaves - producing characteristic marble-sized galls, where the petiole meets the blade of the leaf.