Blumberg received his M.D. degree from Columbia University's College of Physicians and Surgeons and his Ph.D. degree in biochemistry from Oxford University in 1957. In 1960 he became chief of the Geographic Medicine and Genetics Section of the U.S. National Institutes for Health, in Maryland. In 1964 he was appointed associate director for clinical research at the Institute for Cancer Research (later named the Fox Chase Cancer Center) in Philadelphia, and in 1977 he became professor of medicine, human genetics, and anthropology at the University of Pennsylvania. In 1989 he returned to Oxford to become master of Balliol College, a position that he held until 1994. Upon his return to the United States, he resumed his post at the Fox Chase Cancer Center, gaining the title Distinguished Scientist, and continued to teach as professor of medicine and anthropology at the University of Pennsylvania. In May 1999 Blumberg was appointed director of the National Aeronautics and Space Administration (NASA) Astrobiology Institute. He held several different positions while at NASA, where he remained until 2004. The following year he was elected president of the American Philosophical Society.

In the early 1960s Blumberg was examining blood samples from widely diverse populations in an attempt to determine why the members of different ethnic and national groups vary widely in their responses and susceptibility to disease. In 1963 he discovered in the blood serum of an Australian aborigine an antigen that he later (1967) determined to be part of a virus that causes hepatitis B, the most severe form of hepatitis. The discovery of this so-called Australian antigen, which causes the body to produce antibody responses to the virus, made it possible to screen blood donors for possible hepatitis B transmission. Further research indicated that the body's development of antibody against the Australian antigen was protective against further infection with the virus itself. In 1982 a safe and effective vaccine utilizing Australian antigen was made commercially available in the United States.