High-pH drilling fluids invading a formation can change significantly the stress sensitivity of shale. Previous investigations discussed the mechanism of the stress-sensitivity change of shale soaked with alkaline solutions. However, the mechanism for the shale sensitivity change with alkaline solution flow was not examined. In this paper, experiments are conducted on simulation of alkaline solution flow in shale and measurement of the sensitivity change in longitudinally fractured cylindrical plugs. The experimental results show that the sensitivity change passes through four stages as the flow time increases. The stress-sensitivity change is determined by three factors, i.e., hydration swelling, alkali erosion, and particle migration, each of which plays a dominant role in some stage. Hydration swelling determines stress-sensitivity strengthening in stage I because the fracture width is decreased by swollen mineral particles and the roughness of the rock. Alkaline erosion plays the dominant role in stage III because products generated by alkaline erosion and mineral particles destroyed chemically can also decrease the fracture width. Conversely, broken mineral particles migrate with the fluid flow in stages II and IV so that the sensitivity weakening is determined by particle migration. The present work proposes a mechanism for the sensitivity change under the influence of alkaline solution flow and provides theoretical support for the technology of flow-back of high-pH drilling fluids.