During World War II, Huizenga supervised teams at the Manhattan Project in Oak Ridge, Tenn., involved in enriching uranium used in the atomic weapon dropped on Hiroshima in August 1945. During his Argonne years, as a result of examining debris from the "Ivy Mike" nuclear test in 1952, Huizenga was part of the team that added two new synthetic chemical elements, einsteinium and fermium, to the periodic table.  Huizenga and his colleagues were at first unable to publish papers on their discoveries in the open literature, because of classification concerns relating to the nuclear test, but these concerns were eventually resolved and the team was able to publish in Physical Review and thus claim priority for their discovery.  During his Argonne years he was one of the founders of the Gordon Research Conferences on nuclear chemistry, serving as chairman of the nuclear chemistry Gordon Conference in 1958. He received a Guggenheim Fellowship in 1964 and took a sabbatical from Argonne to further his studies as a visiting professor at the University of Paris for the 1964–1965 academic year.
In 1967, he became a professor of chemistry and physics at the University of Rochester where he worked for the remainder of his career, apart from a second Guggenheim Fellowship that allowed him to engage in research during the 1973–1974 school year at the University of California, Berkeley, the Technische Universität München, and the Niels Bohr Institute in Copenhagen.  His research interests at Rochester covered topics in nuclear structure of actinides, nuclear fission, and nuclear reactions between heavy ions.  He was chairman of the Department of Chemistry from 1983 to 1988, retiring as Tracy H. Harris Professor (later Professor Emeritus) of Chemistry.
During Huizenga's time at Rochester, the university had its own particle accelerator, a tandem Van de Graaff accelerator that produced beams of nuclei accelerated to energies of several MeV per nucleon.  This facility, which opened in 1966, afforded him the opportunity to continue his research program in experimental nuclear science.  However, the limited beam energies available led him to more powerful accelerators, such as the SuperHILAC at Berkeley and the Los Alamos Meson Physics Facility, LAMPF, at Los Alamos National Laboratory, for his experimental work.  His LAMPF proposal to study actinide muonic atoms was one of the earliest experiments to receive beam time at the LAMPF stopped-muon facility.
In 1989, Huizenga co-chaired, with Norman Ramsey, a panel convened by the United States Department of Energy which attempted to debunk claims by two University of Utah chemists that they had achieved nuclear fusion at room temperature.  The findings of the Huizenga/Ramsey panel, although highly skeptical of the reality of cold fusion, were cautious:
However, Huizenga later published a book titled "Cold Fusion: The Scientific Fiasco of the Century".