The obvious vibration of a by-pass control valve occurred during the start-up of a nuclear power unit, and several fatigue fracture cases were caused in by-pass valve components due to the excessive valve vibration, which seriously affected the safety operation of the unit. Aiming at this problem, the valve vibration were measured and the numerical simulation of the fluid dynamics inside by-pass valve based on the fluid–structure coupling principle were also carried out. Combined the fluid simulation results and test results, the reasons induced the valve fluid-induced vibration were comprehensively analyzed, and the structure optimization of the by-pass control valve was also performed. The analysis results indicate that: The internal flow characteristics of the by-pass valve are very complex. There are obvious boundary layer separation and vortex shedding phenomena in the valve fluid at different valve openings. The main flow form is turbulence, and the vibration exhibits broadband characteristics. Boundary layer separation and turbulence can cause the buffeting of valve body structure, which may easily lead to fatigue fracture of the valve components after long-term operation. By optimizing the structure of the by-pass valve, the severe valve vibration is reduced significantly, especially the vibration caused by the turbulence flow fluctuations at small valve openings. And the fatigue fracture problem of valve components has also been effectively improved. This work reveals the vibration characteristics of by-pass control valve, and provides references for its structural improvement design and operation mode optimization.