In non-design conditions, severe hydraulic instability can affect the stability of a pump station and even shorten its service life. A Francis pump station in the South-to-North Water Transfer Project was examined to carry out a numerical simulation of the entire flow passage using a bidirectional fluid–solid method for static and fatigue life. Due to the inlet setting, reverse power generation exhibited a more distorted flow pattern that resulted in higher energy loss than the pump condition. The radial force acting on the blades in reverse power generation was 39.1% higher. Runner stress was mainly concentrated at the leading edge and blade edge. The maximum stress in reverse power generation was 35.7 MPa, which was about 28.5% higher than in the pump condition. While the maximum deformation was 0.035 mm, almost 94.4% more severe than in the pump condition, mainly concentrated at the leading edge. Based on the fatigue analysis, a minimum safety factor obtained numerically was 8.238 in the pump condition and 6.343 in the reverse power condition, respectively. The safety factors satisfy the safety standard of the runner material and meet requirements of safety and stability in the reverse power generation condition.