Oscar Riddle is known for his research on evolution, reproduction, heredity, and endocrinology. Riddle is also responsible for isolating the hormone prolactin.

Riddle conducted his research in both the United States and Europe, but spent most of his career at the Station for Experimental Evolution at Cold Spring Harbor, Long Island. His extensive study of birds included investigations into the physiology of reproduction, the basis of sex, as well as breeding, heredity, and evolution. In 1932, while working with pigeons at Cold Spring Harbor's Biological Laboratory, he isolated the hormone, prolactin, which is responsible for stimulating the mammary glands to produce milk in females.

Riddle wrote several papers on the physiology of sex, heredity, and endocrinology, as well as development and reproduction issues. One of his most famous treatises, "Any Hereditary Character and the Kinds of Things We Need to Know About It," discusses the diversity of traits contained in one hereditary characteristic. The paper also questions the limitations faced by the scientists in the field of genetics during his time, especially when dealing with matters of heredity and evolution. Riddle asserted that in order to gain understanding in those areas, it was necessary to thoroughly understand the nature of one individual hereditary character.

Riddle was a member of several biological societies in South America, India, France, England, and the United States. In 1958, he was given the Humanist of the Year award by the American Humanist Association. A confirmed atheist, Riddle called religion a "cult of superstition" in his book, Unleashing of Evolutionary Thought. Riddle was president of the American Rationalist Federation from 1959 to 1960.