From 1975 to 1999, Osterholm served in various roles at the Minnesota Department of Health (MDH), including as state epidemiologist and Chief of the Acute Disease Epidemiology Section from 1984 to 1999. While at the MDH, Osterholm strengthened the departments role in infectious disease epidemiology, notably including numerous foodborne disease outbreaks, the association between tampons and toxic shock syndrome (TSS), and the transmission of hepatitis B and human immunodeficiency virus (HIV) in healthcare workers. Other work included studies regarding the epidemiology of infectious diseases in child-care settings, vaccine-preventable diseases (particularly Haemophilus influenzae type b and hepatitis B), Lyme disease, and other emerging and re-emerging infections.
From 2001 through early 2005, Osterholm, in addition to his role at CIDRAP, served as a Special Advisor to then–HHS Secretary Tommy G. Thompson on issues related to bioterrorism and public health preparedness. In April 2002, Osterholm was appointed to the interim management team to lead the Centers for Disease Control and Prevention (CDC), until the eventual appointment of Julie Gerberding as director on July 3, 2002. Osterholm was asked by Thompson to assist Gerberding on his behalf during the transition period. He filled that role through January 2003.
Osterholm was appointed by Michael Leavitt, Secretary of the Department of Health and Human Services (HHS), to the National Science Advisory Board on Biosecurity in 2005.
Osterholm has been particularly outspoken on the lack of international prepardness for an influenza pandemic. Osterholm has also been an international leader against the use of biological agents as weapons targeted toward civilians. In that role, he served as a personal advisor to the late King Hussein of Jordan. Under Osterholm's leadership, CIDRAP has served as a partner in the Department of Homeland Security's BioWatch program since 2003.
In March 2017 Osterholm and coauthor Mark Olshaker published the critically acclaimed Deadliest Enemy: Our War Against Killer Germs. Richard Preston, author of The Hot Zone and The Demon in the Freezer, writes of the book, "When Osterholm tells us that the potential for global pandemics is a life-or-death issue for every person on the planet, we need to listen. Deadliest Enemy is a powerful and necessary book that looks at the threat of emerging diseases with clarity and realism, and offers us not just fear but plans." In April 2017 MinnPost published a two-part interview (part 1, part 2) with Osterholm about the book.
In 2001, Osterholm provided a comprehensive and pointed review of America's state of preparedness for a bioterrorism attack in his New York Times best-selling book, Living Terrors: What America Needs to Know to Survive the Coming Bioterrorist Catastrophe.
His invited papers in the journals Foreign Affairs, the New England Journal of Medicine, and Nature detailed the threat of an influenza pandemic before the 2009-10 pandemic and the steps we must take to better prepare for such events. He has also published multiple commentaries in The New York Times, most recently on the repercussions of reductions in funding for research and vaccine development, and how this affects our ability to respond to new infectious disease threats. He is the author of more than 315 papers and abstracts, including 21 book chapters.
Osterholm has received numerous honors for his work, including honorary doctorates from Luther College and Des Moines University, and is a member of the Institute of Medicine of the National Academy of Sciences.
He has received numerous honors for his work, including the Pump Handle Award, Council of State and Territorial Epidemiologists (CSTE); the Charles C. Shepard Science Award, CDC; the Harvey W. Wiley Medal, Food and Drug Administration (FDA); the Squibb Award, Infectious Diseases Society of America (IDSA); Distinguished University Teaching Professor, Environmental Health Sciences, School of Public Health, University of Minnesota; and the Wade Hampton Frost Leadership Award, American Public Health Association. He also has been the recipient of six major research awards from the National Institutes of Health (NIH) and the CDC.
Osterholm is a frequently invited guest lecturer on the topic of epidemiology of infectious diseases. He serves on the editorial boards of nine journals, including Infection Control and Hospital Epidemiology and Microbial Drug Resistance: Mechanisms, Epidemiology and Disease, and he is a reviewer for 24 additional journals, including the New England Journal of Medicine, the Journal of the American Medical Association, and Science.
Osterholm was the Principal Investigator and Director of the NIH-supported Minnesota Center of Excellence for Influenza Research and Surveillance (2007-2014) and chaired the Executive Committee of the Centers of Excellence Influenza Research and Surveillance network.
He is past president of the CSTE and has served on the CDC's National Center for Infectious Diseases Board of Scientific Counselors from 1992 to 1997. Osterholm served on the Institute of Medicine (IOM) Forum on Microbial Threats from 1994 through 2011. He has served on the IOM Committee on Emerging Microbial Threats to Health in the 21st Century and the IOM Committee on Food Safety, Production to Consumption, and he was a reviewer for the IOM Report on Chemical and Biological Terrorism. As a member of the American Society for Microbiology, Osterholm has served on the Committee on Biomedical Research of the Public and Scientific Affairs Board, the Task Force on Biological Weapons, and the Task Force on Antibiotic Resistance. He is a frequent consultant to the World Health Organization, the NIH, the FDA, the Department of Defense, and the CDC. He is a fellow of the American College of Epidemiology and the IDSA.