In this work, three types of natural clays including kaolinite, montmorillonite, and illite with different molecular structures, as adsorbents, are selected for the removal of methylene blue dye, and their performance is investigated. Also the optimization and the analysis of the dye adsorption mechanism are performed using the response surface methodology, molecular modeling, and experimental studies. The response surface optimization results demonstrate that the parameters affecting on the dye adsorption process are somewhat similar in all the three types of clays, and any difference in the impacts of the different parameters involved depends on the different structures of these three types of clays. The results of the experimental studies show that all the three clays follow the Temkin isotherm, and the comparison of the clay adsorption capacity is illite (3.28) > kaolinite (4.15) > montmorillonite (4.5) L/g. On the other hand, the results obtained from the laboratory studies and the response surface optimization were obtained using molecular modeling with the Gaussian and Chem-Office softwares. The results of these achievements confirm that the number of acceptor hydrogen bonds around the clays influence the adsorption capacity of methylene blue. Based on the results obtained, most adsorption capacities of clays are related to illite > kaolinite > montmorillonite that have 24, 18, and 16 acceptor hydrogens, respectively. The assessment of the adsorption mechanism process by the different methods confirms the dominance of the physical adsorption process and a minor effect of the chemical adsorption.