SIGLEC15, a critical immune receptor in chickens, plays a crucial role in immune responses to infections, including Newcastle Disease (ND). This study aims to explore the potential of polyphenols as inhibitors of SIGLEC15-mediated Newcastle Disease Virus (NDV) binding to enhance immunity in chickens. Polyphenols are bioactive plant-derived compounds known for their ability to modulate immune receptors and influence signaling pathways. Molecular docking was conducted on 12,000 polyphenols to identify those with high binding affinity for SIGLEC15. Among the screened compounds, Quercetin and Resveratrol demonstrated superior docking scores (-9.45 kcal/mol and -8.79 kcal/mol) and lower RMSD values (0.58 and 0.71, respectively) compared to synthetic SIGLEC15 inhibitors. These polyphenols effectively disrupted the binding sites of NDV on SIGLEC15, inhibiting critical receptor–ligand interactions necessary for viral entry. The NF-κB signaling pathway, activated by SIGLEC15–ligand interactions, was identified as a key pathway modulated by polyphenols. Molecular dynamics simulations (MDS) confirmed the stability of polyphenol–SIGLEC15 complexes, indicating sustained interactions that block NDV invasion. Pharmacokinetic analysis showed favorable profiles, including non-toxicity, high bioavailability, and potential for immune enhancement. By targeting SIGLEC15 and interrupting NDV binding through the NF-κB pathway, these findings provide a novel strategy to improve immunity and protect chickens from Newcastle Disease Virus.