Single crystal (SC) turbine blade adopts directional solidification casting, traditional design approach requires the [0 0 1] crystal orientation coincide with the blade stacking axis, and the principal deviation angle is less than 10 deg, the other crystal orientation is random. This design philosophy result in random fatigue life of the formed blade even in the same service environment. Crystal orientation effect on mechanical response of a SC turbine blade is investigated using finite element calculation, then presents a multi-fidelity optimization procedure for crystal orientation optimizations of the blade. A nonlinear turbine blade FEM model with orientation dependent crystal plastic theory and coupled temperature conversion provides the high-fidelity model, the low-fidelity model involves a surrogate model technique. Through the multi-fidelity optimization of crystal orientation design, taking into account the efficiency and accuracy to reduce the maximum resolved shear stress (Rss) at the dangerous position of solid turbine blade and effectively improve the fatigue life of the blades. The results demonstrate that crystal orientation have an appreciable variation on Rss in the dangerous position of solid turbine blade. The influence of temperature and structure must be taken into consideration, especially the maximum Rss has the significant effect on evaluating the fatigue life of turbine blade. The optimization model based on the approximation theory can accurately describe the response between the design variables and optimization targets. The optimization reduces the Rss and deformation by 28% and 17%, respectively. The multi-fidelity optimization strategy can effectively optimizes the crystal orientation of the blade and improves the blade life.