Cyclin dependent kinases (CDKs) have appeared as an important drug targets over the years with diverse therapeutic potentials. With the objective of designing new chemical entities with enhanced inhibitory potencies against CDK 2 (CDK2) and CDK 4 (CDK4), the 3D-QSAR CoMFA study carried out on indenopyrazole derivatives as inhibitors of these kinases is presented here. The developed model showed a strong correlative and predictive capability having a cross validated correlation co-efficient of 0.747 for CDK4 and 0.755 for CDK2 inhibitions. The conventional and predictive correlation co-efficients were, respectively, found to be 0.913 and 0.760 for CDK4, 0.941 and 0.765 for CDK2. The models could be employed to design ligands with enhanced inhibitory potencies and/or to predict the potencies of analogues to guide synthesis.