The species is widespread in continental North America, with local populations found throughout subarctic Canada and the United States.

Polyphemus moths are considered to be very polyphagous, meaning they eat from a wide variety of plants.

It lays flat, light-brown eggs on the leaves of a number of host trees, preferring Ulmus americana (American elm), Betula (birch), Salix (willow), but also, more rarely, can survive on other trees, including: Quercus (oak), Acer (maple), Carya (hickory), Fagus (beech), Gleditsia triacanthos (honey locust), Juglans (walnut), Pyrus (pear), Prunus (plum, peach, apricot, cherry, etc.

Two broods generally hatch each year throughout the United States, one in early spring and one in late summer.

In captivity, this moth is much more difficult to breed than other American saturniids such as Hyalophora cecropia, Callosamia promethea, or Actias luna.

Kept in a cage, the male and female tend to ignore each other, unless a food plant (particularly oak leaves) is present.

This involves the large eyespots on its hindwings, which give the moth its name (from the cyclops Polyphemus in Greek mythology).

When it leaps, a flash of bright yellow appears on its hind legs, usually startling the predator away from its prey.)

Distraction patterns are believed to be a form of mimicry, meant to misdirect predators by markings on the moths' wings.

The pattern on the hindwings of the Polyphemus moth resembles that on the head of the great horned owl (Bubo virginianus).