The investigation of the crack propagation in as-extruded and heat-treated Mg-Dy-Nd-Zn-Zr alloy with a focus on the interaction of long-period stacking-ordered (LPSO) structures is the aim of this study. Solution heat treatment on a hot extruded Mg-Dy-Nd-Zn-Zr (RESOLOY®) was done to change the initial fine-grained microstructure, consisting of grain boundary blocky LPSO and lamellar LPSO structures within the matrix, into coarser grains of less lamellar and blocky LPSO phases. C-ring compression tests in Ringer solution were used to cause a fracture. Crack initiation and propagation is influenced by twin boundaries and LPSO lamellae. The blocky LPSO phases also clearly hinder crack growth, by increasing the energy to pass either through the phase or along its interface. The microstructural features were characterized by micro-and nanohardness as well as the amount and location of LPSO phases in dependence on the heat treatment condition. By applying nanoindentation, blocky LPSO phases show a higher hardness than the grains with or without lamellar LPSO phases and their hardness decreases with heat treatment time. On the other hand, the matrix increases in hardness by solid solution strengthening. The microstructure consisting of a good balance of grain size, matrix and blocky LPSO phases and twins shows the highest fracture energy.