De Kay returned to Oyster Bay, New York, giving up medicine for the study of natural history.

On the outbreak of cholera in New York City, De Kay hastened to give his services to the afflicted, although the practice of his profession was repugnant to him.

As a result, from 1842 to 1844 he published the multi-volume Zoology of New York, or The New-York Fauna covering: mammals, birds, reptiles and amphibians and fish.

In order to best represent the animals, Hill and De Kay early on decided to use a camera lucida for the rough drafts of the drawings.

De Kay collected the first specimen of a species of small brown snake on Long Island, which was named for him as Storeria dekayi (Holbrook, 1836).