A number of CCK2 antagonists have been reported to play an important role in controlling gastric acid-related conditions, nervous system related disorders and certain types of cancer. To obtain the helpful information for designing potent antagonists with novel structures and to investigate the quantitative structure-activity relationship of a group of 62 different CCK2 receptor antagonists with varying structures and potencies, CoMFA, CoMSIA, and HQSAR studies were carried out on a series of 1,3,4-benzotriazepine-based CCK2 receptor antagonists. QSAR models were derived from a training set of 49 compounds. By applying leave-one-out (LOO) cross-validation study, cross-validated rcv2 values of 0.673 and 0.608 and non-cross-validated (rncv2) values of 0.966 and 0.969 were obtained for the CoMFA and CoMSIA models, respectively. The predictive ability of the CoMFA and CoMSIA models was determined using a test set of 13 compounds, which gave predictive correlation coefficients (rpred2) of 0.793 and 0.786, respectively. HQSAR was also carried out as a complementary study, and the best HQSAR model was generated using atoms, bonds, hydrogen atoms, and chirality as fragment distinction with fragment size (2-5) and six components showing rcv2 and rnv2 values of 0.744 and 0.918, respectively. CoMFA steric and electrostatic, CoMSIA hydrophobic and hydrogen bond acceptor fields, and HQSAR atomic contribution maps were used to analyze the structural features of the datasets that govern their antagonistic potency.