Based on the engineering practices used in mining the protective coal seam at Huainan coalfield in China, this study investigates the temporal evolution of three-dimensional stress of the protected coal seam by numerical simulation. The coal body of the protected coal seam should first be loaded and then unloaded with the three-dimensional stress being reduced simultaneously. In accordance with the forcing process around the coal body of the protected coal seam, permeability experiments were performed under fixed axial displacement with unloading confining pressure (FADUCP) and fixed deviatoric stress with unloading confining pressure (FDSUCP) stress paths. During the loading stage before the unloading point, the permeability and axial strain have a negative exponential relationship. However, during the unloading stage after the unloading point, the permeability and axial strain have a positive exponential relationship. Using the relationship between permeability and axial strain, along with the swelling and deformation of the protected coal seam, the permeability distribution characteristics for the protected coal seam was obtained. According to the permeability distribution characteristics of the protected coal seam, drilling designs for gas drainage can be optimized. Finally, the rationality of the drilling design was verified using gas data measured during mining of the protected coal seam.