Shale permeability will change with the variation of reservoir pressure and formation stress, especially when natural fractures occur failure due to pressure and stress perturbation during hydraulic fracturing, the permeability will change dramatically. So far, however, there is no comprehensive theoretical method could estimate the rock permeability change with natural fractures failure under true-triaxial stress condition. This paper aims to propose a numerical method to investigate the influence of pore pressure, triaxial stress, and natural fractures failure on the shale rock permeability. Firstly, this paper built a digital shale core cylinder by combining the discrete element method (DEM) and fluid-solid coupling model. Then, all the micro parameters of the digital rock were delicately calibrated according to the quasi-triaxial compression tests data of real rock core collected from Bakken shale formation, making the macro-mechanical property and seepage characteristic of digital rock are consistent with real shale rock. Then, based on the calibrated micro-parameters, we constructed a digital core cube to simulate the permeability test under true triaxial conditions. Finally, some natural fractures, as the weak planes, were preset in digital core, and the shale rock permeability change was analyzed with natural fractures failure. It shows that the intact shale permeability will decrease with triaxial stress increasing or pore pressure decreasing. Besides, the permeability of shale will be affected by the natural fractures’ property and failure states. In general, as the triaxial stress increases, the natural fractures in shale rock cube will occur failure gradually, meanwhile, its permeability will rise remarkably in the beginning. However, after most of the natural fractures have occurred failure under high-stress or high-pressure, shale permeability will turn to decrease as the stress continues to increase. This paper explores the inner mechanism and exterior behavior of shale permeability dependence on triaxial stress, pore pressure, and natural fractures failure. • A digital core modeling method is proposed based on the discrete element method. • The digital shale core is constructed and it is identical to a real shale core from Bakken formation. • A series of permeability tests simulation are conducted on the digital shale core cube under true-triaxial stress conditions. • The mechanism of shale permeability dependence on stress, pressure, and natural fractures failure is explored. • This research is beneficial to the fracturing design in shale reservoirs.