Romer, who was born at White Plains, New York, and educated at Amherst College and Columbia University, established his reputation with a PhD on comparative myology (musculature), which remains a classic in its field. The impetus for subsequent paleontological fieldwork and research came with his appointment as associate professor in the University of Chicago's department of geology and paleontology, where he was able to study the collections of late Paleozoic fishes, amphibians, and reptiles. Professor of biology at Harvard from 1934, Romer then became Harvard's director of biological laboratories (1945) and director of the Museum of Comparative Zoology (1946).

One of the major figures in paleontology since the 1930s, Romer spent the greater part of his career researching the evolution of vertebrates, based on evidence from comparative anatomy, embryology, and paleontology, and his work has had considerable influence on evolutionary thinking, especially with regard to the lower vertebrates. He paid particular attention to the relationship between animal form and physical function and environment, tracing, for example, the physical changes that occurred during the evolutionary transition of fishes to primitive terrestrial vertebrates. He made extensive collections of fossils of fishes, amphibians, and reptiles from South Africa and Argentina and from the Permian deposits in Texas. His best-known publication is Man and the Vertebrates (1933), subsequently revised as The Vertebrate Story (1959).