While diverse strains of low-pathogenicity avian influenza have circulated in wild birds for a long period of time, there has previously been little pathology in wild birds, ducks have been the primary and largely asymptomatic wild reservoir, and spillover into mammals has been limited and rare. In recent years, a high-pathogenicity avian influenza (HPAI) virus has emerged on the global scene and shifted the previously established dogmas for influenza infection. High-pathogenicity avian influenza has expanded into wildlife in unprecedented numbers and species diversity, with unmatched disease severity for influenza in wildlife. As the disease ecology of influenza has shifted with this new variant, significant efforts are underway to understand disease course, pathology, and species susceptibility. Here we focus primarily on the impact that HPAI has had in wild mammals while framing these novel spillovers within the context of significantly expanding disease in avian species and geography. The clinical and pathology presentations of HPAI in these atypical hosts are discussed, as well as prognosis and risk for continued spillover. The companion Currents in One Health by Runstadler and Puryear, AJVR, May 2024, provides further context on viral reservoirs and possible routes of direct or environmental transmission and risk assessment of viral variants that are emerging within wildlife.