This research emphasizes a new modeling approach by Box Behnken Design in Response Surface Methodology (RSM) for the optimization of chalcones yield based to the elaborated nanomaterials. Palladium nanoparticles (PdNPs) supported on prepared mesoporous TiO2 (Titania) are used as an ecological alternative and a new heterogeneous catalyst for the preparation and optimization of chalcones via Claisen-Schmidt Condensation (CSC). The yield of the chalcone reactions was mathematically described as a function of three parameters: PdNPs concentration, temperature and time reaction. Based on a statistical modeling and optimization process, the optimal conditions were mainly reached at the following levels: a PdNPs concentration of 0.1 wt% with a reaction temperature of 65 °C and 40 min of time. This configuration allowed reaching 99% of chalcone yield. Indeed, the results of chalcone reactions of different aromatic aldehydes in the same optimal conditions show that 0.1 wt%Pd/TiO2 catalyst is found to be highly active. Overall, the value of the adjusted coefficient of determination (R2) equal to 0.9961 indicated that the considered model was quite suitable and that the selected methodology was very efficient throughout the optimizing process. The catalyst recycle analysis shows that the PdNPs supported on Titania can be reused four consecutive times without a decrease in catalytic activity. As a general statement, this study has developed a convenient procedure for the preparation of chalcone compound in a short period of time. Moreover, the proposed approach can be served as a model in the context of green chemistry.