Molecular docking plays an indispensable role in predicting the receptor-ligand interactions in which the protein receptor is usually kept rigid, whereas the ligand is treated as being flexible. Because of the inherent flexibility of proteins, the binding pocket of apo receptors might undergo significant conformational rearrangement upon ligand binding, which limits the prediction accuracy of docking. Here, we present an iterative anisotropic network model (iterANM)-based ensemble docking approach, which generates multiple holo-like receptor structures starting from the apo receptor and incorporates protein flexibility into docking. In a validation data set consisting of 233 chemically diverse cyclin-dependent kinase 2 (CDK2) inhibitors, the iterANM-based ensemble docking achieves higher capacity to reproduce native-like binding poses compared with those using single apo receptor conformation or conformational ensemble from molecular dynamics simulations. The prediction success rate within the top5-ranked binding poses produced by the iterANM can further be improved through reranking with the molecular mechanics-Poisson-Boltzmann surface area method. In a smaller data set with 58 CDK2 inhibitors, the iterANM-based ensemble shows a higher success rate compared with the flexible receptor-based docking procedure AutoDockFR and other receptor conformation generation approaches. Further, an additional docking test consisting of 10 diverse receptor-ligand combinations shows that the iterANM is robustly applicable for different receptor structures. These results suggest the iterANM-based ensemble docking as an accurate, efficient, and practical framework to predict the binding mode of a ligand for receptors with flexibility.