Crutzen conducted research primarily in atmospheric chemistry. He is best known for his research on ozone depletion. In 1970 he pointed out that emissions of nitrous oxide (), a stable, long-lived gas produced by soil bacteria, from the Earth's surface could affect the amount of nitric oxide (NO) in the stratosphere. Crutzen showed that nitrous oxide lives long enough to reach the stratosphere, where it is converted into NO. Crutzen then noted that increasing use of fertilizers might have led to an increase in nitrous oxide emissions over the natural background, which would in turn result in an increase in the amount of NO in the stratosphere. Thus human activity could affect the stratospheric ozone layer. In the following year, Crutzen and (independently) Harold Johnston suggested that NO emissions from the fleet of, then proposed, supersonic transport (SST) airliners (a few hundred Boeing 2707s), which would fly in the lower stratosphere, could also deplete the ozone layer; however more recent analysis has disputed this as a large concern.
He listed his main research interests as "Stratospheric and tropospheric chemistry, and their role in the biogeochemical cycles and climate". From 1980, he worked at the Department of Atmospheric Chemistry at the Max Planck Institute for Chemistry, in Mainz, Germany; the Scripps Institution of Oceanography at the University of California, San Diego; and at Seoul National University, South Korea. He was also a long-time adjunct professor at Georgia Institute of Technology and research professor at the department of meteorology at Stockholm University, Sweden. From 1997 to 2002 he was professor of aeronomy at the Department of Physics and Astronomy at Utrecht University.
He co-signed a letter from over 70 Nobel laureate scientists to the Louisiana Legislature supporting the repeal of that U.S. state's creationism law, the Louisiana Science Education Act. In 2003 he was one of 22 Nobel laureates who signed the Humanist Manifesto.
, Crutzen had an h-index of 151 according to Google Scholar and of 110 according to Scopus. On his death, the president of the Max Planck Society, Martin Stratmann, said that Crutzen's work led to the ban on ozone-depleting chemicals, which was an unprecedented example of Nobel Prize basic research directly leading to a global political decision.