Highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b viruses spread efficiently via migratory wild birds and increasingly infect mammals. The leopard cat (Prionailurus bengalensis) is an endangered mesopredator in South Korea that frequents wetland–forest ecotones and overlaps with wild waterbirds, placing it at risk of exposure. We describe a fatal HPAI H5N1 infection in a free-ranging leopard cat detected through national wildlife surveillance during a period of widespread H5N1 activity in wild birds along the East Asian–Australasian Flyway. The animal showed acute neurological and respiratory signs and died shortly after rescue. H5 viral RNA was detected by RT-qPCR in all examined tissues, with the highest load in the brain, and infectious virus was isolated from the brain, bronchoalveolar lavage fluid, and nasal swab. Pathology revealed acute serofibrinous pneumonia, severe nonsuppurative meningoencephalitis, necrotizing vasculitis with thrombosis, and necrotizing enteritis with secondary mesenteritis. Immunohistochemistry demonstrated abundant viral antigen in nasal and olfactory epithelium, olfactory bulb, neurons, endothelial cells, and bronchial and bronchiolar epithelium, supporting combined olfactory and hematogenous dissemination. This clinicopathological description expands the spectrum of HPAI-associated lesions in felids and underscores the value of wild carnivores as bioindicators of avian influenza spillover in a One Health context.