Cancer remains one of the leading causes of death globally, driving the need for effective therapies. Targeting cyclin-dependent kinase 2 (CDK2), a critical cell cycle regulator, is a promising approach for cancer treatment. This study developed a new group of 5-methylisatin derivatives with strong binding potential to CDK2. By combining the isatin core with various benzoylhydrazide substituents, the design process was guided by molecular docking, dynamic simulations, and ADMET analysis. Thirty-one derivatives were modelled, and a subset was synthesised and characterised for their physicochemical and spectroscopic properties. The analysis suggested that substitutions at R2 and R3 positions improved binding affinity, while modifications at R4 were less favourable. Hydrogen bonds with GLU81 and LEU83, along with hydrophobic interactions, were key to stabilising the complexes. A comparison with a reference molecule (