The technology of natural gas dehydration with ionic liquids (ILs) as a promising method was proposed and systematically investigated in this work. The IL [EMINI] [Tf2N] was screened out as an appropriate absorbent from 252 IL candidates for the natural gas dehydration process by means of the COSMO-RS model. The sigma-profiles and sigma-potentials of the CH4-H2O-IL system were analyzed at the molecular level to explain the possibility of CH4 dehydration using [EMIM][Tf2N] as absorbent. The experiment data of CH4 solubility in pure IL and in the mixture of IL + H2O were measured and compared with the predicted results by the UNIFAC-Lei model. Moreover, the CH4 dehydration experiment was carried out, and the gas product with a low water content (down to 350 ppm in mole fraction) can be obtained. Finally, the conceptual dehydration process. was simulated and optimized using the rigorous equilibrium (EQ) stage model, into which the UNIFAC-Lei model parameters were input. It was found that the CH4 dehydration process with [EMIM] [Tf2N] demonstrates the better separation performance, i.e., no solvent loss, plant miniaturization, and saving energy consumption, when compared to the benchmark triethylene glycol (TEG) process. Thus, ILs can be taken on as a type of promising alternative absorbents to conventional solvents in the field of gas dehydration.