Abstract: The main reservoirs of oil and gas are in the pores and fractures of rocks. Under deep and complex stress environments, reservoir rock fracture permeability evolution directly affects the flow of oil and gas, which is an important research object of oil and gas exploration and development. In order to study the permeability evolution of fractured rock under complex stress paths, a permeability test of a single sample in the process of loading and unloading complex stress paths was performed using high-precision hydro-mechanics coupled with triaxial experimental equipment. The experimental scheme entails permeability tests under (i) increasing confining pressure; (ii) increasing liquid pressure; (iii) cyclic loading and unloading deviatoric stress; and (iv) increasing confining pressure and deviatoric stress synchronously. The results show that liquid flow in fractured mudstone can be regarded as laminar flow with low velocity. The sample containing more fracture (R2) has a significantly higher permeability and stress sensitivity. The permeability changes with both liquid and confining pressure as a function of positive and negative exponential functions. The increase in deviatoric stress leads to a decrease in permeability, and unloading causes permeability to increase. The whole evolution of permeability is irreversibly reduced. During the increasing confining pressure and deviatoric stress stage, permeability also decreases, and tends to stabilize. Under a confining pressure of 10.3 MPa, permeability remains basically constant. Therefore, based on the double medium model of fracture, the permeability evolution model of fractured rock was proposed considering the interaction among fracture system, matrix system, and the expansion deformation of fracture under external stress. The simulation results of the model are in good agreement with the experimental results. These results can provide an important theoretical basis for the prediction of permeability evolution of fractured mudstone and efficient oil and gas exploitation.