In 2020, highly pathogenic avian influenza (HPAI) isolates from clade 2.3.4.4b emerged in Europe and spread globally, including in bovine hosts in the USA. Viruses from this clade cause minimal disease in dairy cattle, characterized by decreased milk production but low mortality rates. Infections have also occurred in feline hosts. In contrast to cows, infection of cats (and closely related species, including skunks and foxes) can result in severe neurological signs and mortality. Documented feline H5N1 infections from clade 2.3.4.4.b have a mortality rate of approximately 80% following rapid onset of clinical signs. No antiviral compounds have been tested in an experimental feline model; however, anecdotal clinical evidence suggests early treatment with oseltamivir may improve outcomes in felines with HPAI. Here, we show the in vitro efficacy of several influenza inhibitors in feline glial astrocyte (PG-4) and kidney (CRFK) cell culture models using the clade 2.3.4.4.b virus Tx2/24 (H5N1). The neuraminidase inhibitor oseltamivir carboxylate did not effectively inhibit viral replication in either cell line. The cap-dependent endonuclease inhibitor baloxavir exhibited the strongest inhibition of this virus, with EC50 values of 30 nM in PG-4 and 1 μM in CRFK cells. Amantadine and rimantadine, M2 ion channel inhibitors, were unable to completely inhibit viral replication in either cell line at any concentration utilized. The broad-spectrum nucleoside analog GS-441524 demonstrated little to no inhibition of viral replication in either cell line. Additionally, the mutagenic NHC analogs EIDD-1931 and EIDD-2801 successfully inhibited viral replication at the maximum tested concentration of 100 μM but exhibited significant cytotoxicity. Our findings suggest that baloxavir should be considered by veterinary clinicians as the first-line drug of choice when presented with felines or other species infected with HPAI.