With increasing demands for coal resources, coal has been gradually mined in deep coal seams. Due to high gas content, pressure and in situ stress, deep coal seams show great risks of coal and gas outburst. Protective coal seam mining, as a safe and effective method for gas control, has been widely used in major coal-producing countries in the world. However, at present, the relevant problems, such as gas seepage characteristics and optimization of gas drainage borehole layout in protective coal seam mining have been rarely studied. Firstly, by combining with formulas for measuring and testing permeability of coal and rock mass in different stress regimes and failure modes in the laboratory, this study investigated stress–seepage coupling laws by using built-in language Fish of numerical simulation software FLAC^3D. In addition, this research analyzed distribution characteristics of permeability in a protected coal seam in the process of protective coal seam mining. Secondly, the protected coal seam was divided into a zone with initial permeability, a zone with decreasing permeability, and permeability increasing zones 1 and 2 according to the changes of permeability. In these zones, permeability rises the most in the permeability increasing zone 2. Moreover, by taking Shaqu Coal Mine, Shanxi Province, China as an example, layout of gas drainage boreholes in the protected coal seam was optimized based on the above permeability-based zoning. Finally, numerical simulation and field application showed that gas drainage volume and concentration rise significantly after optimizing borehole layout. Therefore, when gas is drained through boreholes crossing coal seams during the protective coal seam mining in other coal mines, optimization of borehole layout in Shaqu Coal Mine has certain reference values.