In the effort to conserve energy and reduce emissions, waste heat recovery for power generation offers a significant advantage by enabling energy recycling. The turbo-expander, a critical component within expansion power generation systems, plays a pivotal role. However, flow during various operation can generate vibrations that negatively affect operational efficiency and trigger safety hazards. Therefore, studying the flow-induced vibration of the turbo-expander is of significant value. We apply computational fluid dynamics (CFD) and transient structural mechanics to examine the flow-induced vibration characteristics of the turbo-expander influenced by stator-rotor interaction using a two-way fluid structure interaction (FSI) strategy. The flow field modeling and calculation approach discussed here is validated through actual operating data from a prototype. Subsequent stages involve coupling the steady-state flow field with the structural field and performing pre-stress modal analysis on the impeller. In the end, we integrate flow-induced excitation from flow field calculations with the transient structural field to calculate the impeller’s flow-induced vibration at the expansion end of the turbo-expander. Our analysis reveals that guide vane frequency (3267 Hz), its harmonic frequencies, and pre-stress modal frequency (1465 Hz) prominently manifest in pressure pulsation and the dynamic response of the turbo-expander impeller under the influence of stator-rotor interaction.