Following the Nobel Prize ceremony in Stockholm, Fermi, his wife Laura (who was Jewish), and their children emigrated to the United States to escape the growing anti-Semitism and political repression in Fascist Italy. He accepted a position at Columbia University in New York City.

Upon learning of the discovery of nuclear fission by Otto Hahn and Fritz Strassmann, Fermi immediately recognized its potential for creating a nuclear chain reaction and alerted the U.S. government to the possibility of atomic weapons.

Fermi moved to the University of Chicago to join the Metallurgical Laboratory, part of the top-secret Manhattan Project, which aimed to develop an atomic bomb before Germany.

Under Fermi's leadership, the first self-sustaining nuclear chain reaction was achieved in Chicago Pile-1 (CP-1), a crude nuclear reactor built beneath the football stadium at the University of Chicago. This historic event marked a turning point in the development of nuclear technology.

Fermi became a naturalized citizen of the United States, solidifying his commitment to his new home.

Fermi played a crucial role at the Los Alamos National Laboratory, working on various aspects of the atomic bomb project, including calculations related to critical mass and explosion dynamics. He witnessed the Trinity test, the first nuclear weapon detonation.