Born in Neisse (now Nysa in Poland), Bloch was educated at the Technical University, Munich, and – after his emigration to America in 1936 – at Columbia University, New York, where he obtained his PhD in 1938. He then taught at Columbia until 1946, when he moved to the University of Chicago, becoming professor of biochemistry there in 1950. In 1954 Bloch accepted the position of Higgins Professor of Chemistry at Harvard, a post he retained until his retirement in 1978.

In 1940 the important radioisotope carbon–14 was discovered by Martin Kamen and Samuel Ruben. Bloch was quick to see that it could be used to determine the biosynthesis of such complex molecules as cholesterol, a basic constituent of animal tissues characterized by four rings of carbon atoms. Thus in 1942, in collaboration with David Rittenberg, Bloch was able to confirm the earlier supposition that cholesterol was partly derived from the two-carbon acetate molecule.

The many steps through which acetate develops into the 27-carbon cholesterol took years of analysis to establish. The breakthrough came in 1953, when Bloch and R. Langdon identified squalene as an intermediate in cholesterol synthesis. Squalene, a terpene with an open chain of 30 carbon atoms, initiates the folding necessary to produce the four rings of cholesterol. For this work Bloch shared the 1964 Nobel Prize for physiology or medicine with Feodor Lynen.