Newcastle Disease (ND), caused by specific strains of the ApMV-1 virus, represents a major challenge in poultry agriculture, with high mortality rates and the capability to infect over 241 avian species. In Indonesia, ND remains endemic, causing recurring outbreaks that severely impact the poultry industry. Despite vaccine availability, limitations such as incomplete efficacy, frequent administration, and the risk of virulence reversion highlight the necessity of developing novel antiviral compounds. This study investigates the green synthesis and antiviral potential of 4-(4-hydroxy-3,5-dimethylphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (THPM) against the Newcastle Disease Virus (NDV). THPM was synthesized using the Biginelli reaction, a one-pot, solvent-free process involving a keto ester, urea, and aldehyde, adhering to green chemistry principles by minimizing waste and eliminating harmful solvents. In ovo antiviral activity of THPM was assessed using embryonated chicken eggs infected with NDV. Hemagglutination assays revealed significant viral inhibition, with the highest efficacy observed at 10 µg/mL, achieving a 95.77% inhibition rate. H-NMR structural analysis confirmed the presence of key functional groups essential for antiviral action, and structural resemblance of THPM to nucleic acids likely contributes to its selective activity. This study underscores the importance of eco-friendly antiviral agents like THPM in addressing the limitations of the current ND management. Future research should focus on optimizing THPM’s efficacy and safety to develop sustainable solutions for controlling Newcastle Disease.