Lewis was born in Wilkes-Barre, Pennsylvania and graduated from E.L. Meyers High School. He received a BA in Biostatistics from the University of Minnesota in 1939, where he worked on Drosophila melanogaster in the lab of C.P. Oliver. In 1942 Lewis received a Ph.D. from California Institute of Technology (Caltech), working under the guidance of Alfred Sturtevant. After serving as a meteorologist in the U.S. Air Force in World War II, Lewis joined the Caltech faculty in 1946 as an instructor. In 1956 he was appointed Professor of Biology, and in 1966 the Thomas Hunt Morgan Professor of Biology. Among his many awards were the Thomas Hunt Morgan Medal (1983), the Gairdner Foundation International award (1987), the Wolf Foundation prize in medicine (1989), the Rosenstiel award (1990), the National Medal of Science (1990), the Albert Lasker Award for Basic Medical Research (1991), and the Louisa Gross Horwitz Prize (1992).
His Nobel Prize winning studies with Drosophila founded the field of developmental genetics and laid the groundwork for our current understanding of the universal, evolutionarily conserved strategies controlling animal development. He is credited with development of the complementation test. His key publications in the fields of genetics, developmental biology, radiation and cancer are presented in the book Genes, Development and Cancer, which was released in 2004.