Research and development of multi-target inhibitors has attracted increasing attention as anticancer therapeutics. B-Raf(V600E) synergistically works with vascular endothelial growth factor receptor 2 (KDR) to promote the occurrence and progression of cancers, and the development of dual-target drugs simultaneously against these two kinds of kinase may offer a better treatment advantage. In this paper, docking and three-dimensional quantitative structure activity relationship (3D-QSAR) studies were performed on a series of dual B-Raf/KDR inhibitors with a novel hinge-binding group, [5,6]-fused bicyclic scaffold. Docking studies revealed optimal binding conformations of these compounds interacting with both B-Raf and KDR. Based on these conformations, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models were constructed, and the best CoMFA (q(2) = 0.542, r(2) = 0.989 for B-Raf; q(2) = 0.768, r(2) = 0.991 for KDR) and CoMSIA models (q(2) = 0.519, r(2) = 0.992 for B-Raf; q(2) = 0.849, r(2) = 0.993 for KDR) were generated. Further external validations confirmed their predictability, yielding satisfactory correlation coefficients (r(pred)(2) = 0.764 (CoMFA), r(pred)(2) = 0.841 (CoMSIA) for B-Raf, r(pred)(2) = 0.912 (CoMFA), r(pred)(2) = 0.846 (CoMSIA) for KDR, respectively). Through graphical analysis and comparison on docking results and 3D-QSAR contour maps, key amino acids that affect the ligand-receptor interactions were identified and structural features influencing the activities were discussed. New potent derivatives were designed, and subjected to preliminary pharmacological evaluation. The study may offer useful references for the modification and development of novel dual B-Raf/KDR inhibitors.