Wu and Yuan were married at the home of Robert Millikan, Yuan’s academic supervisor and the President of Caltech, on May 30, 1942. Neither the bride’s nor the groom’s families were able to attend due to the outbreak of the Pacific War. Wu and Yuan moved to the East Coast of the United States, where Wu became an assistant professor at Smith College, a private women’s college in Northampton, Massachusetts, while Yuan worked on radar for RCA.

She found the job frustrating, as her duties involved teaching only, and there was no opportunity for research. She appealed to Lawrence, who wrote letters of recommendation to a number of universities. Smith responded by making Wu an associate professor and increasing her salary. She accepted a job from Princeton University in New Jersey as the first female faculty member in the history of the physics department, where she taught officers of the navy.

In March 1944, Wu joined the Manhattan Project’s Substitute Alloy Materials Laboratories at Columbia University. The role of the SAM Laboratories, headed by Harold Urey, was to support the Manhattan Project’s gaseous diffusion (K-25) program for uranium enrichment. Wu worked alongside James Rainwater in a group led by William W. Havens Jr., whose task was to develop radiation detector instrumentation. In September 1944, Wu was contacted by the Manhattan District Engineer, Colonel Kenneth Nichols. Wu was frustrated with her lack of professorships and volunteered to help out in the project. In the beginning, Wu was assigned to check the radiation effect of the reactor by building her own instruments; later, however, she was contacted for a much bigger role. The newly commissioned B Reactor, the first practical nuclear reactor ever built, which was located at the Hanford Site had run into an unexpected problem, starting up and shutting down at regular intervals. John Archibald Wheeler and partner Enrico Fermi suspected that a fission product, Xe-135, with a half-life of 9.4 hours, was the culprit, and might be a neutron poison or absorber.