In this study, the aerodynamic uncertainty analysis and optimization of a conventional axisymmetric vehicle with an aerodynamic configuration were investigated. The prediction precision of the typical aerodynamic performance estimating methods, namely, engineering estimation and numerical simulation, was compared using the wind tunnel test data of the vehicle. Then, using a modified missile data compendium (DATCOM) software, a high-efficiency and high-precision method was developed, which was applied to analyze and characterize the aerodynamic parameters of the axisymmetric vehicle. To enhance the robustness and reliability of aerodynamic performance, an uncertainty-based design optimization (UDO) framework was established. The design space was scaled by parameter sensitivity analysis, and improved computational efficiency was achieved by developing parallel polynomial chaos expansions (PCEs). The optimized results show that the modified method exhibits high accuracy in predicting aerodynamic performance. For the same constraints, the results of the deterministic design optimization (DDO) showed that compared with the initial scheme, the probability of the controllability-to-stability ratio satisfying the constraint decreased from 98.8% to 72.4%, and this value increased to 99.9% in the case of UDO. Compared with the results of the initial scheme and DDO, UDO achieved a considerable reduction in mean values and standard deviation of aerodynamic performances, which can ensure a higher probability of constraints meeting the design requirements, thereby, realizing a reliable and robust design.