The novelty of this research lies in the development of unprecedented pyrimidinone-based scaffolds, prepared through simple synthetic routes, and their evaluation as promising inhibitors of the hepatitis A virus. Also, we introduce a new synthetic method for scaffold 5 that is driven by nanoscience. Among the several compound nanoparticles used in catalytic applications, nickel oxide nanoparticles are the most important and intriguing nanomaterials. Through reactions of 5 with different amines, aliphatic aldehydes, aliphatic halo carbonyls, and anhydrides, this approach made it possible to create a novel series of pyrimidinone derivatives. Advanced spectroscopy tools and DFT-based geometry optimization were used in a comprehensive strategy design. Strong binding affinities of the produced compounds to the Hepatitis A virus's 3C protease active site have been demonstrated by molecular docking analyses, indicating that they could potentially have protease inhibitory properties. The pharmacokinetic analysis, including BOILED-Egg modeling and CYP inhibition profiling, confirms the compounds' suitability for oral absorption and highlights potential metabolic interactions. The antiviral efficacy was confirmed by biological examination using MTT assessments on Vero cells, with compound 9b showing the highest activity (64.64 % inhibition at non-toxic concentration). There was also significant inhibition shown by other analogues, such as 13d and 15c. Study of the structure–activity relationship has represented critically important electron-withdrawing groups, fused heterocyclic systems, and lipophilic moieties for strengthening antiviral efficacy. These results highlight the novelty of integrating nanomaterial-assisted synthesis with computational and biological screening to discover promising anti-HAV compounds, establishing pyrimidinone derivatives as strong candidates for future antiviral therapy development.