Frisch, the son of a Viennese printer and publisher, was educated at the University of Vienna where he obtained his doctorate in 1926. He was employed in Berlin (1927–30) at the German national physical laboratory, the Physikalisch Technische Reichsanstalt, and moved to the University of Hamburg in 1930. However, with the introduction of Hitler's racial laws, he was sacked in 1933 and consequently traveled via Copenhagen to England. After working at the universities of Birmingham and Liverpool (1939–43) he moved to America and spent the period 1943–45 at Los Alamos, working on the development of the atom bomb. With the end of the war Frisch worked briefly at the Atomic Energy Research Establishment at Harwell, leaving in 1947 to take up the Jackson Chair of Physics at Cambridge, a post he held until his retirement in 1972.

In 1939 Frisch, with his aunt, Lise Meitner, was closely involved in the crucial discovery of nuclear fission. He spent Christmas in Sweden visiting Meitner, who reported to him some strange results obtained by her former colleague Otto Hahn. Hahn found that when uranium was bombarded with neutrons, one of its decay products was the much lighter element barium. Frisch said that his first reaction was that Hahn had made a mistake, but Meitner was more inclined to trust Hahn's qualities as a good chemist. After some thought and calculation they concluded that this must in fact be what was later called nuclear fission. Frisch rushed back to Copenhagen to inform Niels Bohr who was able to confirm Hahn's experiments. But in all this excitement the most important point had been missed – the mechanism of the neutron chain reaction. However the thought did occur independently to many others.

Frisch did further work on fission while at Birmingham, collaborating with Rudolph Peierls in confirming Bohr's suggestion that a chain reaction would be more likely to result with uranium–235 rather than with the more common isotope, uranium–238. After much work Frisch came to the basic and frightening conclusion that an “explosive chain reaction” could be produced with a pound or two of uranium–235 rather than the tons of it which he first thought would be necessary. Frisch and Peierls were therefore probably the first two people in the world to be aware not just of the possibility of a nuclear bomb but of its practicality. They immediately wrote a report that was sent to Henry Tizard, a scientific adviser to the British government, which Frisch claimed was decisive in getting the British Government to take the atomic bomb seriously.

In 1979 Frisch produced his fascinating and witty memoirs, What Little I Remember.