Zwicky, who was born at Varna in Bulgaria, studied at the Federal Institute of Technology, Zurich, where he obtained his BS in 1920 and his PhD in 1922. He moved to America in 1925, working at the California Institute of Technology and the Mount Wilson and Palomar Observatories until his retirement in 1968. He was associate professor of theoretical physics from 1929 to 1942 and professor of astrophysics from 1942 to 1968.

Zwicky worked in various fields of physics, including jet propulsion and the physics of crystals, liquids, and gases. He is, however, better known for his astronomical research. In 1936 he began an important search for supernovas. These are celestial bodies whose brightness suddenly increases by an immense amount as a result of a catastrophic explosion. They had been observed over several centuries in our Galaxy and one had been detected in the Andromeda galaxy as long ago as 1885. But when Edwin Hubble showed in 1923 that the Andromeda galaxy was about 900,000 light-years away, the question arose as to how anything could appear so bright over such a vast distance.

Zwicky worked out their frequency as about three per millennium per galaxy. Although many have passed unobserved in our Galaxy, five supernovas have been reported since ad 1000, including one in 1054 that produced the Crab nebula, Tycho's star in 1572, and Kepler's star in 1604. Zwicky also showed that supernovas characteristically have an absolute magnitude of –13 to –15, which makes them up to 100 million times brighter than the Sun.

In 1932 Lev Landau introduced the concept of a neutron star into astronomy and in 1934 Zwicky and Walter Baade suggested that these compact superdense objects might be produced in the cores of supernovas. This was later developed by Robert Oppenheimer, G. M. Volkoff, and others in 1939 into an important theory of stellar evolution.

In more recent years Zwicky and his colleagues carefully studied both galaxies and clusters of galaxies. One result of this work is the so-called Zwicky catalog, which gives the positions and magnitudes of over 30,000 galaxies and almost 10,000 clusters lying mainly in the northern-hemisphere sky.