The uncertainty in the casting orientation of single-crystal aeroengine turbine blades is an intractable engineering problem, and breaking through the crystal orientation design technology is vitally important to enhance the fatigue lifetime reliability of the blade. In this paper, a three-dimensional decoupling model for casting orientation is established according to the crystallographic characteristics of single-crystal blade, and the distribution information and statistical features of the orientation deviation angle of single-crystal turbine blades are obtained for the first time according to this decoupling model. Subsequently, the orientation-dependent models and generalized regression neural networks (GRNNs) analysis system of reliability are established, and the analysis of fatigue life response for single-crystal blades in four quadrants is carried out based on the neural network analysis system. Finally, three orientation design schemes are developed, and the improvement effect of each scheme on lifetime reliability are investigated. For the secondary orientation design scheme, the lifetime reliability is improved from 62 % to more than 95 % at the design life of 15,000 cycles; For the integrated orientation design scheme, the life reliability is improved from 50 % to more than 95 % at the design life of 20,000 cycles. The results show that the orientation design can effectively improve the fatigue life reliability of the product, especially in the long-life design interval of 10,000 to 20,000 cycles. Therefore, the orientation design should be highly emphasized in the design of single-crystal turbine blades for aeroengine.