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Highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b continues to circulate extensively among wild birds, poultry, and mammals, presenting ongoing risks at the intersection of human, animal, and environmental health. Antiviral approaches tailored for poultry farming or farm settings are still largely under investigation. The influenza A polymerase acidic (PA) endonuclease, which plays a key role in cap-snatching during viral transcription, is a conserved antiviral target across different host species. This research introduces a computational workflow to detect PA endonuclease inhibitors suitable for veterinary and environmental use. Homology modelling of recent H5N1 clade 2.3.4.4b PA sequences (2021–2025) was performed based on the crystallographic structure 6FS8. A curated ligand library, including reference inhibitors, hydrophilic metal-binding scaffolds, and repurposed antivirals, was screened via cross-host molecular docking against poultry- and mammalian-specific PA models. Docking results highlighted baloxavir and entecavir as top candidates due to their strong and consistent binding profiles across multiple targets. Entecavir showed particularly promising binding affinity in the poultry PA model (−100.6), similar to the reference inhibitor baloxavir (−97.5 to −97.7). A 170 ns molecular dynamics simulation of the poultry PA–entecavir complex indicated stable structural behavior, with RMSD below 1.1 Å, and MM/PBSA calculations gave a binding free energy of ΔG = −85.1 ± 0.8 kJ/mol. Physicochemical analysis revealed entecavir's high polarity and predicted water solubility, suggesting its suitability for water-based or environmental delivery within poultry facilities. Overall, this study introduces a One Health–focused computational framework that integrates cross-host structural modeling, docking, molecular dynamics, and agrochemical suitability filtering to identify promising antiviral candidates for poultry outbreak control. The results point to entecavir as a promising candidate for further evaluation in veterinary antiviral studies.