Lewis acid heterogeneous catalyst, ZnAl2O4/SiO2 nanocomposite, was determined as a strong catalyst for the green and safe three-component reactions by the one-pot procedure. The effect of factors, such as the amount of catalyst, the molar ratio of reactants, reflux time and temperature on the three-component reactions were investigated. Also, the parameters of green chemistry were studied. These reactions under solvent-free conditions in the presence of ZnAl2O4/SiO2 dramatically increased the yield of the formation of dihydropyrimidinones derivatives in a very short time. The results showed that ZnAl2O4/SiO2 under solvent-free conditions greatly accelerate the three-component reactions with the advance of imine pathway and preventing the formation of unwanted side-products. Also, aromatic aldehydes with low electron density had the best outcomes. Lower reaction yield was produced by beta-ketoesters with more steric hindrance. Without noticeably altering reaction time or yield, this catalyst employed six times. The technique is environmentally friendly, as shown by its low E-factor of 0.218-0.570 and high atom economy of 90.025-87.237.