Optimization of the vibration transmission of an internal floating-raft system and the resultant sound radiation of the fluid-loaded cylindrical structure is presented. The influences of different objective functions, fluid loading, external loading, and an optimized frequency band on the optimization results are investigated in detail. The frequency-response-function (FRF)-based substructuring method and the coupled finite element method–boundary element method are employed to study the vibration transmission from vibrating machines to the base and the vibro-acoustic behaviour of the fluid-loaded cylindrical structure respectively. An FRF-based substructuring sensitivity analysis is applied to obtain the optimal values of the stiffness of isolators under five objective functions in the low-frequency range. The optimized results demonstrate that some of the objective functions are equivalent to each other and can be replaced by each other. The reasons for the difference in the variation trends of the stiffness of the lower isolators for different objective functions are discussed in detail. The fluid loading does have an impact on the optimal results and it influences the variation trend of only the stiffness of the isolators that support the machines without an externally applied load. The external loading and the optimized frequency band are two factors to be carefully considered in the design stage. This investigation reveals that it should take into account fluid–structure interaction and comprehensively consider different vibration or acoustic objectives in the design stage.