Nickel-based superalloys exhibit pronounced elastic anisotropy and, hence, the local grain orientation strongly affects the stress and strain distribution in the material under mechanical loadings. Therefore, the crack initiation and failure behaviour of components made from nickel-based superalloys are complex and hardly predictable. A better fundamental understanding of the phenomena that occur in nickel-based superalloys under a quasistatic and cyclic load is therefore desired. Previously, a continuum mechanics-based model has been successfully developed, considering the grain structure, the elastic anisotropy, and the Schmid factor, based on data from electron backscatter diffraction (EBSD). The E·m model was confirmed by the finite element method (FEM) simulations and experimental observations regarding the resulting average stresses and strains in the individual grains as well as the formation of slip bands under a quasistatic load with few restrictions. The behaviour under cyclic loadings has been investigated in this work to correlate the mechanical behaviour, simulated by the previously developed FE models, with the local stiffness and Schmid factors considering fatigue failure. For this purpose, the fatigue behaviour of Inconel 617 samples was characterised up to the high-cycle fatigue (HCF) regime, accompanied by EBSD measurements for stress amplitudes that resulted in strains close to the elastic–plastic regime. The EBSD data were used to create digital twins of the samples to simulate the mechanical reaction to a displacement similar to the associated strain of the fatigue tests. An analysis of the fractured samples by scanning electron microscopy was performed to retrace the location of the crack initiation supported by the EBSD measurements before and after fatigue testing. Two samples were investigated in detail that showed different fracture types. Sample 1 showed transcrystalline failure in a grain that showed a high Young’s modulus, Schmid factor, and resolved shear stress that indicates a failure due to the properties of the grain itself. In contrast, an intercrystalline failure was observed for sample 2 that showed large differences in the orientation and, hence, largely different mechanical properties in the area of failure as well. The observed failure types, the resulting stresses and strains calculated by the FE model, and the consideration of the E·m model showed an agreement of all the methods. Therefore, the findings of this work complement previous investigations of the mechanical behaviour of coarse-grained anisotropic nickel-based superalloys with a focus on the orientations of the grains towards the loading direction.