Rotor–stator interaction (RSI) is a major source of periodic hydraulic excitation in Francis turbines and plays a critical role in vibration, resonance, and fatigue damage of runner structures. Reliable assessment of RSI-induced dynamic behavior requires accurate representation of unsteady flow loads and their interaction with structural dynamics. This study presents an integrated CFD–FSI-based numerical framework for evaluating the vibration response and fatigue integrity of a prototype Francis turbine runner. Unsteady pressure fluctuations were obtained from transient computational fluid dynamics (CFD) simulations and transformed into frequency-domain pressure spectra at multiple monitoring points on the runner blades. These data were systematically preprocessed and mapped onto a full three-dimensional finite element model to perform harmonic response analysis (HRA). Both a pure structural model and an acoustic-based fluid–structure interaction (FSI) model were employed to quantify the effects of fluid added mass and hydrodynamic damping. Static structural analysis, modal analysis, harmonic response analysis in the range of 0–300 Hz, and stress–life (S–N) based fatigue analysis were conducted for rated and partial-load operating conditions. The modal analysis demonstrated substantial reductions in natural frequencies under submerged conditions, with frequency reduction ratios ranging from approximately 60% to 85%, depending on mode shape and vibration direction. Harmonic response analysis identified resonance peaks associated with dominant RSI excitation frequencies. Fatigue analysis confirmed that all critical regions satisfied the design fatigue life criteria with large safety margins. The structural-only model produced conservative predictions, whereas the FSI model provided more realistic dynamic responses at the expense of markedly higher computational cost. The results indicate that a two-stage CFD–FSI strategy—combining rapid structural screening with frequency correction and targeted high-fidelity FSI analysis—offers an effective balance between accuracy and computational efficiency. The proposed methodology contributes to practical CFD–FSI applications in hydraulic turbine design.