Historically considered accidental hosts of influenza A viruses, domestic cats (Felis catus) have gained attention during the global expansion of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b. In addition to traditional exposure via predation on infected wild birds, recent outbreaks have highlighted novel transmission routes, including contaminated commercial raw poultry products and unpasteurised milk. The susceptibility of cats has been linked to the abundant distribution of α-2,3-linked sialic acid receptors in both the respiratory tract and the central nervous system, while adaptive mutations such as PB2-E627K may enhance viral replication efficiency in mammalian hosts. Clinical disease is characterised by severe respiratory, neurological, and ocular manifestations, including acute bilateral amaurosis, and is associated with high mortality rates. Recent documentation of feline-associated zoonotic transmission highlights the importance of surveillance and infection control measures in veterinary settings. Early recognition of compatible clinical syndromes, combined with rapid molecular diagnosis and appropriate biosafety measures, is essential for case management and risk mitigation. This review summarises current insights into the epidemiology, pathogenesis, clinical presentation, diagnosis, and One Health implications of H5N1 infection in domestic cats.