Brown earned his B.A. from the University of Pennsylvania in 1962, and received his M.D. in 1966. After an internship at the Massachusetts General Hospital in Boston (1966-68), he came to the National Institutes of Health (NIH) as a Clinical Associate in Earl Stadtman's laboratory of biochemistry. In 1971 he was appointed assistant professor at the University of Texas Southwestern Medical School, Dallas, and in 1977 he became professor of genetics and director of the Center of Genetic Diseases.
Brown's research interests have included digestive enzymes, particularly their role in the metabolism of cholesterol. However, he is perhaps best known for his studies of lipid receptors on body cells and their importance in removing cholesterol from the blood. Cholesterol is produced by mammalian cells as well as being taken up into cells from food. It is carried in the bloodstream by proteins called LDLs (low-density lipoproteins. commonly known as "bad cholesterol"). Brown worked on the genetic disease hypocholesterolemia. He found that sufferers from the disease lack a receptor on their cell surfaces to which the LDLs bind, and that this problem results in abnormally high levels of cholesterol in the bloodstream.
Brown's research on cholesterol was done in collaboration with Joseph Goldstein, with whom he has had a long and fruitful scientific partnership since 1966. In 1984 Brown and Goldstein elucidated the gene sequence which codes for the LDL receptor, and opened up the possibility of synthesizing drugs to control cholesterol metabolism. They were jointly awarded the 1985 Nobel Prize in Physiology or Medicine.