The structural safety and sealing performance of a triple-eccentric butterfly valve are crucial technical indicators that influence its reliability and service life. In this study, a new multi-objective optimization strategy is proposed to realize a lightweight design of valve trims, reduce the maximum equivalent stress, and reasonably distribute the sealing-specific pressure. A two-stage optimization scheme is designed by combining topology optimization (TO) and response surface methodology optimization (RSM). The topology optimization is employed to allocate the material distribution of the valve trims and provide the parameters for the response surface optimization, while the response surface methodology optimization conducts a further revision and optimization of the structural parameters of the valve trims. The results of the simulation experiments indicate that the maximum equivalent stress of the lightweight designed valve trims is reduced from 290.85 MPa to 99.88 MPa, and the maximum sealing-specific pressure of the sealing surface is reduced from 197.78 MPa to 77.83 MPa. Additionally, a novel approach is presented for assessing the sealing performance using the clearance of the fitting surface. This method can intuitively evaluate the state of metal sealing and guide the design of the fitting tolerance by analyzing the sensitivity of the dimensional deviation to the sealing-specific pressure. The findings demonstrate that the optimized valve exhibits good structural safety and sealing performance.