Highly pathogenic avian influenza A/H5N1 viruses continue to spread among multiple mammalian species, including humans, raising concerns about zoonotic transmission and pandemic preparedness. Immunocompromised individuals often develop severe and prolonged disease, yet evidence guiding antiviral therapy in these patients remains limited. We investigated pathogenesis, transmissibility, and antiviral efficacy of oseltamivir, baloxavir, and molnupiravir against a human A/H5N1 clade 2.3.4.4b genotype D1.1 virus isolated in Canada using a cyclophosphamide-immunosuppressed hamster model. A/H5N1 infection caused severe disease in immunosuppressed hamsters with no contact transmission. Baloxavir conferred complete survival, markedly reduced viral burden, and prevented neuroinvasion, while high-dose molnupiravir and combination therapy with oseltamivir and low-dose molnupiravir improved outcomes and achieved viral clearance in lung and brain tissues. These findings support baloxavir as an effective therapeutic option for severe A/H5N1 infection in immunocompromised hosts and identify molnupiravir as a promising antiviral candidate, with implications for pandemic preparedness strategies targeting vulnerable populations.