As a part of the green mining technology system, the separation grouting technology can play a importment role in reducing the surface subsidence. In view of the serious problems of surface subsidence under the conditions of fully integrated mining of extra-thick coal seams in Xinjiang, effective measures such as separation grouting should be taken to control them. In this paper, the working face of 1101 of Zhundong No.2 Mine is taken as the research background, the key layers and quantities of overburden are calculated through the theory of key layers, and the possible horizons of the separation are predicted, and then the stable and effective separation space horizon is obtained by calculating the development height of the water conduction fracture zone, so as to determine the separation grouting horizon. Subsequently, according to the migration law of overburden and the development characteristics of separation during the advancement of the working face, the best time for grouting was determined. Then, according to the double integral of the deflection curve of the thin plate under uniform load, the space volume of the separation layer is solved, so as to preliminarily predict the size of the separation grouting amount.Finally, the above calculations are verified based on the results of numerical simulation analysis and the measured microseismic data. It is concluded that the key layer 2 should be selected for the horizon of separation grouting and grouting should be carried out between the mining of the working face and 200m~220m. Finally, it is concluded that the separation grouting volume is about 1.03×104m3. The separation grouting volume calculated from the simulation results is 0.89×104m3, and the error is 13.6%.