The purpose of mining subsidence prediction is to establish a reliable assessment for surface subsidence resulting from underground mining. In this study, a new method for predicting subsidence in two-seam mining is proposed. First, the surface subsidence due to mining the upper seam is monitored. Then, taking the subsidence data as indicators, the optimal mechanical parameters of overlying strata can be obtained by orthogonal experimental design and inverse analysis of numerical simulation. Finally, further subsidence is calculated and predicted by the numerical model. A case of two-seam underground mining is studied using this methodology. This coal mine is located in the Dongsheng coal field in Inner Mongolia, China. Based on GPS surface subsidence monitoring and parameter inversion, the subsidence induced by two-seam mining is estimated and predicted. This study shows that the ratio of the height of overlying strata to mining thickness (H/M), mining configuration and adjacent mining have a significant effect on the surface subsidence caused by two-seam mining. By parameter inversion, the proposed optimal parameters can be applied to predict the subsidence of a nearby mine with similar stratigraphic conditions. Furthermore, this methodology can also be used to predict the subsidence caused by mining of more than two seams.