The structural stability and fatigue of the runner of a high-head pump-turbine was explored by conducting a numerical simulation of the entire flow passage under different working conditions. A two-way fluid-structure interaction calculation method was used, which captured the values for 5.75 fn, 9 fn, 13 fn, 18 fn, and 20 fn ( fn is rotational frequency) in pressure fluctuation. The resonance of the runner was compared with the results of the modal analysis. The rain flow and damage accumulation methods were used to predict the fatigue life. The study found that the 13 fn pressure fluctuation of the fluid in the flow passage of the pump-turbine is the primary cause of the resonance of the runner blade. The main frequency of vibration is the third natural frequency of the runner. The vibration form is up and down along the Z–axis, and there are some high-order resonances. The most vulnerable part of the entire runner is located at the T-shaped connection between the blade inlet edge and the runner crown and bottom ring. The excitation force under the small flow condition is more complicated than that under the large flow condition, which is more likely to cause fatigue damage to the runner. In addition, the damage extent of the high-stress amplitude to the runner is obviously greater than the influence of the number of stress cycles, accounting for approximately 60% of the total damage. The research results can provide a reference for the operational stability and life prediction of a high-head pump-turbine runner.