Abstract This article describes the first detections of disease due to natural infection with highly pathogenic avian influenza virus (HPAIv) H5N1 of the Eurasian lineage goose/Guangdong clade 2.3.4.4b in wild terrestrial mammals throughout the United States during 2021-2022. Affected mammalian species include 50 red foxes ( Vulpes vulpes ), 6 striped skunks ( Mephitis mephitis ), 4 raccoons ( Procyon lotor ), 2 bobcats ( Lynx rufus ), 2 Virginia opossums ( Didelphis virginiana ), 1 coyote ( Canis latrans ), 1 fisher ( Pekania pennanti ), and 1 gray fox ( Urocyon cinereoargenteus ). Infected mammals primarily exhibited neurological signs. Necrotizing meningoencephalitis, interstitial pneumonia, and myocardial necrosis were the most common lesions; however, species variations in lesion distribution were observed. Genotype analysis of sequences from 48 animals indicates that these cases represent spillover infections from wild birds.