During the atomic bombing of Hiroshima, on August 6, 1945, Agnew, along with Alvarez and Johnston, flew as a scientific observer in The Great Artiste, piloted by Charles Sweeney, which tailed the Enola Gay as the instrumentation aircraft. Agnew later recalled, "After we dropped our gauges I remember we made a sharp turn to the right so that we would not get caught in the blast – but we still got badly shaken up by it." He brought along a movie camera and took the only existing movies of the Hiroshima event as seen from the air.
A proponent of tactical nuclear weapons, Agnew pointed out in 1970 that the Thanh Hoa Bridge in Vietnam required hundreds of sorties to destroy with conventional weapons when a nuclear weapon could have done the job with just one.
In a 2005 BBC interview, Agnew stated, "About three-quarters of the U.S. nuclear arsenal was designed under my tutelage at Los Alamos. That is my legacy."