Brown was born in Brooklyn, New York, the son of Evelyn, a homemaker, and Harvey Brown, a textile salesman. Graduated from Cheltenham High School (Wyncote, PA). Brown graduated from the University of Pennsylvania in 1962 and received his M.D. from the University of Pennsylvania School of Medicine in 1966.

Their findings led to the development of statin drugs, the cholesterol-lowering compounds that today are used by 16 million Americans and are the most widely prescribed medications in the United States. Their discoveries are improving more lives every year, both in the United States and around the world[needs citation]. New federal cholesterol guidelines will triple the number of Americans taking statin drugs to lower their cholesterol, reducing the risk of heart disease and stroke for countless people. Following these important advances, their team of dedicated researchers elucidated the role of lipid modification of proteins (protein prenylation) in cancer. In 1984 he was awarded the Louisa Gross Horwitz Prize from Columbia University together with Joseph L. Goldstein (Co-recipient of 1985 Nobel Prize in Physiology or Medicine). In 1988, Brown received National Medal of Science for his contributions to the world of Medicine.

In 1993, their trainees Xiaodong Wang and Michael Briggs purified the Sterol regulatory element binding proteins (SREBPs). Since 1993, Drs. Brown, Goldstein, and their colleagues have described the unexpectedly complex machinery by which cells maintain the necessary levels of fats and cholesterol in the face of varying environmental circumstances. Dr. Brown holds The W. A. (Monty) Moncrief Distinguished Chair in Cholesterol and Arteriosclerosis Research; is a Regental Professor of the University of Texas; holds the Paul J. Thomas Chair in Medicine; and is a member of the Board of Scientific Directors at The Scripps Research Institute. Frequently mentioned as a candidate for nationally-prominent positions in scientific administration, Dr. Brown, like his colleague Joseph L. Goldstein, elects to continue hands-on involvement with research, leading a research team that typically includes a dozen doctoral and postdoctoral trainees. He and his colleague are among the most highly cited Scientists in the world.

Brown is also on the prestigious Prix Galien USA Committee that "recognizes the technical, scientific and clinical research skills necessary to develop innovative medicines". The inauguration of the Prix Galien in the US, the equivalent of the Nobel Prize in this field, was in September 2007, and the winners were selected by a preeminent scientific and learned committee that included 7 Nobel laureates, of which Brown was one.