Neuraminidase inhibitors (NAIs) and cap-dependent endonuclease inhibitors (CENIs) represent two classes of antiviral drugs recommended for early treatment of patients with seasonal influenza A virus (IAV) infections. However, only limited human data, particularly on combination antiviral treatment, are available to inform optimal dosing regimens against novel IAVs, including highly pathogenic avian influenza A(H5N1) virus, associated with severe disease. Clade 2.3.4.4b A(H5N1) viruses have caused outbreaks in avian and mammalian species worldwide, highlighting the need to assess antiviral drug efficacy against these strains. We challenged ferrets with a D1.1 genotype A(H5N1) virus and treated infected animals with the NAI oseltamivir phosphate (OST) and the CENI baloxavir acid (BXA), alone or in combination, with treatment onset commencing pre- or post-symptom onset (24- or 48-hours post-inoculation (p.i.), respectively). When administered pre- or post-illness onset, BXA, but not OST, monotherapy provided significant reduction of clinical signs and significantly decreased infectious viral levels (in both respiratory and extrapulmonary specimens) compared with mock-treated animals. Combination OST/BXA treatment, when administered pre- or post-symptom onset, resulted in significant improvements in both metrics versus OST monotherapy. These data support continued investigation of antiviral treatment modalities that include both NAI and CENI for patients with mild and severe A(H5N1) disease.