Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is an important therapeutic target for the treatment of asthma, chronic obstructive pulmonary disease, allergic rhinitis and atopic dermatitis. In this study, we report the binding site analysis of CRTh2 through molecular docking and quantitative structure–activity relationship (QSAR) studies to explore the interaction of 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl) acetic acid derivatives. Various comparative models were generated using the available crystal structure of human delta opioid receptor (4N6H) as the template, and benzylthio acetic acid derivatives were docked into the predicted binding site region of human CRTh2 receptor. Surflex docking studies enabled us to identify that K5.43, Y4.60, N185, Y6.51, Q5.36, E6.58, T7.38 and H6.52 residues were the most crucial amino acids interacting with the ligand. In addition to docking, atom-by-atom matching and structure-based 3D-QSAR method CoMFA was performed. Based on better q 2 and r 2 pred values, the best predictions were obtained for the ligand-based (q 2 = 0.552, r 2 pred = 0.636) and for receptor-based (q 2 = 0.507, r 2 pred = 0.541) QSAR model, whose robustness and predictability were verified by external test set validation. The results correlate well with the previously reported mouse model, and our study serves as a guide for mutational studies of human CRTh2 and further experimental investigations on the synthesis of new CRTh2 antagonist.