Abstract: Due to prolonged and repeated flights at high Mach numbers, aircraft geometric layout deformation is induced by the accumulated comprehensive force/thermal effects. In this study, the cumulative thermal deformation effect of the fuselage is treated as an uncertainty input. Uncertainty quantification and modeling are conducted and integrated into the aerodynamic layout optimization process. A robust optimization model for high-speed aircraft has been developed in this paper, along with a proposed solution strategy. Four distinct optimization models were solved, compared, and analyzed, thereby verifying the robustness of the model and the efficacy of the solution approach. Simulation results indicate that the accuracy of aerodynamic predictions is significantly influenced by the cumulative thermal deformation effect. Consequently, the propagation of predictive deviation can disrupt the optimization convergence direction, thereby impacting the final optimal configuration.