New derivatives of hydrazone have been successfully created, specifically 2-(1-(Aryl)-5-methoxy-2-methyl-1H-indol-3-yl)-N'-(2-chlorobenzylidene) acetohydrazide. The transformation of Indomethacin ester into hydrazide was achieved through a reaction with hydrazine hydrate in absolute ethanol, followed by the reaction of the resulting hydrazide with aromatic aldehydes. The structures of these newly synthesized hydrazones were validated through IR, 1HNMR, and 13CNMR analyses. Each compound's energies were optimized by utilizing density functional theory (DFT) for theoretical calculations. By employing a quantitative structure-activity relationship (QSAR) mathematical model, this optimization enables the prediction of the biological activity of the compounds. Therefore, this research centers on the synthesis and characterization of hydrazone derivatives of Indomethacin, emphasizing the use of QSAR modeling to connect biological activity and molecular structure. The study sheds light on the methods employed for compound synthesis and characterization, contributing valuable insights into the properties and potential applications of these innovative derivatives through the application of computational chemistry.