A finite element method, boundary element method, and genetic algorithm combined method is developed for the optimization of natural frequencies of fluid-loaded plates. In this method, the coupled finite element method-boundary element method is used for the free flexural vibration analysis of plates with arbitrary fluid loading effects and arbitrary elastic boundary conditions, and the genetic algorithm method is combined with the finite element method-boundary element method for searching the optimal values of plate's boundary parameters. By using this method, multiple natural frequencies of a given fluid-loaded plate can be optimized simultaneously to different target values. The coupled finite element method-boundary element method is first validated by comparing with earlier published results. The proposed optimization method is then applied to the optimal boundary condition design of four different cases. The results show natural frequencies of a fluid-loaded plate are sensitive to its boundary conditions. The possibility of optimizing the natural frequencies of a fluid-loaded plate by modifying boundary conditions is demonstrated, as well as the effectiveness of the proposed method as a structural optimization tool. According to the authors' knowledge, this study is the first attempt of optimizing fluid-loaded plate natural frequencies by considering arbitrary boundary conditions as optimization variables.