Adult northern cardinals are predated by Felis silvestris, Canis familiaris, Accipiter cooperii, Lanius ludovicianus, Lanius excubitor, Sciurus carolinensis, Asio otus and Otus asio. Nestlings and eggs are vulnerable to predation by snakes, birds and small mammals. Egg and nestling predators include Lampropeltis doliata, Coluber constrictor, Elaphe obsoleta, Cyanocitta cristata, Sciurus niger, Tamiasciurus hudsonicus and Tamias striatus. Molothrus ater also remove eggs from the nest, sometimes eating them.

When confronted with a predator near their nest, both male and female northern cardinals will give an alarm call that is a short, chipping note, and fly toward the predator in an attempt to scare them away. They do not aggressively mob predators. (Halkin and Linville, 1999)