Nowadays, obesity has been becoming one of the most popular problems to the global health. Molecular design with the aid of computing method is an efficient and cost-saving solution in the initial research of new potential drugs for the treatment of obesity. This study focused on benzyl amino chalcone derivatives as they have a benzyl group that can mimic the hydrophobic effect of the long chain carbon of Orlistat, a drug used to treat obesity. Initially, 102 molecular structures were prepared and docked into the protein by using AutoDock Vina version 1.5.6. Fourteen structures having good docking scores were selected to synthesize using a Claisen-Schmidt reaction. Afterward, these synthesized chalcones were tested biological activity against pancreatic lipase by spectrophotometric determination at a wavelength of 405 nm, using p-nitro phenyl palmitate as the substrate. The co-crystallized ligand of pancreatic lipase enzyme was redocked into the enzyme and the RMSD was 1.4976 Å which showed the ligand and the protein preparation could regenerate the practical experiment. As the docking results, the binding affinities of top ten compounds varied from -8.6 and -10.2 kcal/mol. Biological testing resulted in 4 derivatives with IC50 >120 µM, 8 derivatives with 60 µM < IC50 < 120 µM and 2 derivatives with IC50 < 60 µM. In addition, the docking results also confirmed the key role of amino acid Ser152 in interacting with the ligands. The benzyl amino chalcone derivatives are required for further investigation to become a lead compound for anti-obesity drug discovery.