This paper describes the method used in the depleted reservoir for analyzing horizontal in-situ stresses in order to define a stable mud weight window to maximize the efficiency of drilling process. The method combines wellbore stability modeling, in-situ stress prediction, and pore pressure depletion during production process. In the presence of any hydraulically isolated fault blocks or other permeability barriers, the pore pressure depletion will cause horizontal stress changes in both magnitude and orientation. Furthermore, the changes of horizontal stress affect the wellbore stability of inclined wells. The results indicate that the reservoir depletion has notable effect on the safe mud weight window, especially the fracture pressure. The fracture pressure may be overestimated in previous model, and the most stable well azimuth is not static but varies over the lifetime of the oilfield. The research conclusions can provide significant reference for the mud weight design of directional well in depleted reservoir.