This dataset includes epidemiology, clinical signs, gross and microscopic pathology, and virology data from two red foxes (Vulpes vulpes) and one fisher (Pekania pennanti) submitted to the USGS-National Wildlife Health Center for cause-of-death determination and confirmed positive for highly pathogenic avian influenza (HPAI) H5N1 by USDA’s National Veterinary Services Laboratories. The foxes were juveniles from North Dakota and the fisher was an adult from Wisconsin. Clinical signs included neurological deficits such as ataxia, lethargy, or paralysis. Gross and microscopic lesions included myocardial pallor, pulmonary and hepatic congestion, meningoencephalitis, interstitial pneumonia, myocardial necrosis, and hepatic necrosis. Highly pathogenic avian influenza H5N1 2.3.4.4 was detected in swabs and/or organ tissues by PCR; genotype B3.1 was identified in the foxes and B3.2 was identified in the fisher. Death of all three animals was attributed to HPAI.