The Aurora kinases have been regarded as attractive targets for the development of new anticancer agents. Recently a series of azaindole derivatives with Aurora B inhibitory activities were reported. To explore the relationship between the structures of substituted azaindole derivatives and their inhibition of Aurora B, 3D-QSAR and molecular docking studies were performed on a dataset of 41 compounds. 3D-QSAR, including CoMFA and CoMSIA, were applied to identify the key structures impacting their inhibitory potencies. The CoMSIA model showed better results than CoMFA, with r(2)(cv) value of 0.575 and r(2) value of 0.987. 3D contour maps generated from CoMFA and CoMSIA along with the docking binding structures provided enough information about the structural requirements for better activity. Based on the structure-activity relationship revealed by the present study, we have designed a set of novel Aurora B inhibitors that showed excellent potencies in the developed models. Thus, our results allowed us to design new derivatives with desired activities.