Components made from coarse-grained alloys often exhibit crack initiation in the far field of notches or bore holes when subjected to static and cyclic loading at high temperature or under thermo-mechanical fatigue (TMF) conditions. It is often the combination of elevated stress and a weak spot in the microstructure that defines the site of crack initiation, rather than the local stress concentration alone. This is partly due to the mismatch between grain orientations and the local anisotropic deformation behavior. Since the grain size of such nickel alloys for use in turbine engines is usually in the range of several millimeters, it is possible to macroscopically investigate the local deformation behavior of individual grains using digital image correlation (DIC). In this study, flat specimens with bore holes were subjected to TMF and low-cycle fatigue (LCF) loads up to a maximum temperature of 950°C with dwell times in an induction-heated servo-hydraulic test setup. To measure the local strain development and crack initiations, a stereo digital camera DIC setup was used. After testing, the grain structure in the gauge section of the specimens was analyzed by electron backscatter diffraction (EBSD) measurements and transformed into a microstructure-based finite element analysis model. Data processing and microstructure reconstruction were done by the Matlab toolbox MTEX by creating a geometrical model and subsequently meshing in Gmsh. The stress distribution in the gauge section was recalculated by applying anisotropic, linear-elastic material properties to identify possible crack initiation sites. As a result, the initiation behavior of primary and secondary cracks in specimens that experienced creep damage during the experiment was clarified. The orientation of the following crack propagation can be associated with the microstructure and the observed deformation behavior of the crystallites.