Thermal Protection System (TPS) is a critical component of space vehicles to protect them from damage by extreme aerothermal heating conditions. The uncertainty of the aerothermal heating conditions, including approaching velocities, atmospheric density, pressure, etc., significantly affects the aerothermal heating imposed on the TPS, vastly changing the initial design conditions. In this study, we developed a new uncertainty quantitative (UQ) analysis method to comprehensively consider all the uncertainty of TPS materials, structures, and aerothermal heating conditions. To address the challenges of a massive amount of input and determined optimization parameters, we first induced the response surface method and Monte Carlo algorithm to produce a large number of analysis samples for Probabilistic Design. Then, the key affecting factors, not all the input design parameters, were chosen for optimization with sequential optimization and reliability assessment (SORA) strategy by a sensitivity analysis. With such improvements, the optimization for UQ analysis becomes practical. We used this new UQ method to analyze the effects of uncertainty of the aerothermal heating conditions on the thermal protection layer. A variable thickness design is proposed to adapt the non-uniform aerothermal heating conditions for the TPS. The results show that significant light-weighting can be achieved without the reliability penalty. The optimized structure also reduces internal temperature gradients and facilitates a more uniform temperature field distribution for the TPS. This study provides a new UQ engineering design approach for the system with many designed parameters.