Cyclin D dependent kinases 4/6 regulate the entry of cells into S phase and are effective target for the discovery of anticancer drugs. In this article, 3D-QSAR modeling including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis fields (CoMSIA) was implemented on 52 dual CDK4/6 inhibitors. As a result, we obtained a pretty good 3D-QSAR model, which is CoMFA_CDK4 with q² to be 0.543 and r² to be 0.967; CoMSIA_CDK4 with q² being 0.518 and r² being 0.937; CoMFA_CDK6 with q² to be 0.624 and r² to be 0.984; CoMSIA_CDK6 with q² being 0.584 and r² being 0.975. Molecular docking confirmed the important residues for interactions. Molecular dynamics simulation further confirmed binding affinity with key residues of protein, such as Lys22, Lys35, Val96 for CDK4 and Lys43, His100, Val101 for CDK6 at the active sites. Then these results offered new directions to explore new inhibitors of CDK4/6. Finally, we designed 10 novel compounds with promising expected activity and ADME/T properties, and provided referable synthetic routes.