Born in South Bend, Indiana, he attended John Carroll Catholic High School in Birmingham, AL before attending the University of Notre Dame for his undergraduate studies (B.S., biology), and Yale University (Ph.D., biology) for his graduate work. In 1978, he moved to his first independent job, at the European Molecular Biology Laboratory in Heidelberg, Germany and moved from Heidelberg to Princeton University in the United States in 1981.
Much of his research has focused on embryogenesis in the fruit fly Drosophila melanogaster, specifically in the patterning that occurs in the early Drosophila embryo. Most of the gene products used by the embryo at these stages are already present in the unfertilized egg and were produced by maternal transcription during oogenesis. A small number of gene products, however, are supplied by transcription in the embryo itself. He has focused on these "zygotically" active genes because he believes the temporal and spatial pattern of their transcription may provide the triggers controlling the normal sequence of embryonic development.
In 1995, he was awarded the Nobel Prize in Physiology or Medicine with Edward B. Lewis and Christiane Nüsslein-Volhard as co-recipients, for their work revealing the genetic control of embryonic development.
Wieschaus taught for Duke University's Program in Genetics and Genomics.
As of 2005, Wieschaus is the Squibb Professor in Molecular Biology at Princeton, and Adjunct Professor of Biochemistry at the University of Medicine and Dentistry of New Jersey – Robert Wood Johnson Medical School.