Thermal insulation structure is a key factor to protect a high-speed aircraft to work safely and complete various tasks. The multilayer thermal insulation (MTI) structure has attracted much attention because of its light weight and good thermal insulation effect. The performance of an MTI structure is not only related to its physical sizes, but also closely related to the material optimization and temperature influences. A transient nonlinear thermal transfer model of the MTI structure is established, and a numerical solution strategy of the nonlinear thermal transfer model is proposed. Considering material selection, introducing the temperature influence of materials, and taking the geometric dimensions and equivalent mechanical properties of the MTI structures as constraints, an optimization frame of the MTI structures is established. Then two intelligent methods are adopted to solve the problem. Using the aerodynamic heating environment of X-43 flight trajectory, the results of a typical high-speed aircraft show that the proposed optimization framework can reduce the structural mass density from 13.95 kg‧m−2 to 9.10 kg‧m−2 by about 34.8 %. The temperature effect analysis shows that the temperature variation has an important influence on the optimization results. If the temperature effect on material properties is not considered, the optimized design scheme may not meet the temperature design constraints (The maximum temperature of the inner surface is 410 K, far exceeding the maximum allowable temperature of 320 K) which further leads to structural failures. Finally, the reliability and rationality of the optimization scheme are verified by a finite element model (FEM). The equivalent modulus of the optimized MTI structure is 146 GPa and the mass area density of the MTI structure is 7.7 kg‧m−2. The optimization design method of an MTI structure proposed in the current paper provides a technical support and lays a foundation for the overall design of a high-speed aircraft.