The purpose of this study was to explore the three-dimensional quantitative structure-activity relationships (3D-QSAR) and the pharmacophore model of a new class of potent activators of the anthranilic diamide ryanodine receptor (RyR), comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and distance comparison technique (DISCOtech) were performed on 38 anthranilic diamides. Successful CoMFA and CoMSIA models yielded “leave-one-out” (LOO) cross-validated correlation coefficient (q2) values of 0.785 and 0.788 and non-cross-validated correlation coefficient (r2) values of 0.958 and 0.981, respectively. Results were graphically interpreted in terms of field contribution maps. A DISCOtech pharmacophore model containing an aromatic ring center, a hydrophobic ring center, a hydrogen bond-donor and a hydrogen bond-acceptor was constructed. This model indicated that hydrophobic interaction and hydrogen bonds have important roles in the interactions between activators and RyRs, which was consistent with CoMSIA results. The information obtained from CoMFA, CoMSIA and DISCOtech models enabled interpretation of the structure-activity relationships of anthranilic diamides. Based on the constructed models, some vital features for the interaction of anthranilic diamides with RyRs were identified, which may prove helpful in designing more potent RyR activators.