MGluR2 is G protein-coupled receptor that is targeted for diseases like anxiety, depression, Parkinson’s disease and schizophrenia. Herein, we report the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of a series of 1,3-dihydrobenzo[ b][1,4]diazepin-2-one derivatives as mGluR2 antagonists. Two series of models using two different activities of the antagonists against rat mGluR2, which has been shown to be very similar to the human mGluR2, (activity I: inhibition of [(3)H]-LY354740; activity II: mGluR2 (1S,3R)-ACPD inhibition of forskolin stimulated cAMP.) were derived from datasets composed of 137 and 69 molecules respectively. For activity I study, the best predictive model obtained from CoMFA analysis yielded a Q2 of 0.513, R2ncv of 0.868, R2pred = 0.876, while the CoMSIA model yielded a Q2 of 0.450, R2ncv = 0.899, R2pred = 0.735. For activity II study, CoMFA model yielded statistics of Q2 = 0.5, 2ncv = 0.715, R2pred = 0.723. These results prove the high predictability of the models. Furthermore, a combined analysis between the CoMFA, CoMSIA contour maps shows that: (1) Bulky substituents in R7, R3 and position A benefit activity I of the antagonists, but decrease it when projected in R8 and position B; (2) Hydrophilic groups at position A and B increase both antagonistic activity I and II; (3) Electrostatic field plays an essential rule in the variance of activity II. In search for more potent mGluR2 antagonists, two pharmacophore models were developed separately for the two activities. The first model reveals six pharmacophoric features, namely an aromatic center, two hydrophobic centers, an H-donor atom, an H-acceptor atom and an H-donor site. The second model shares all features of the first one and has an additional acceptor site, a positive N and an aromatic center. These models can be used as guidance for the development of new mGluR2 antagonists of high activity and selectivity. This work is the first report on 3D-QSAR modeling of these mGluR2 antagonists. All the conclusions may lead to a better understanding of the mechanism of antagonism and be helpful in the design of new potent mGluR2 antagonists.