Recently, several types of nacre-like materials have been developed using various methods. However, the resulting materials exhibit a significant randomness and defects compared to natural nacre. Therefore, evaluating the influence of these microstructural variations on the material’s mechanical behavior is of high interest for the development of nacre-like materials and their industrial scale-up. In this work, we present an original method that allows the modeling of complex morphology of brick and mortar materials, by combining Discrete Element Method and Electron Backscatter Diffraction images. Using different realistic microstructures we studied the effect of the microstructural variations on crack propagation and damage resistance. The obtained results were compared to the regular microstructure of nacre and showed a non-negligible decrease of mechanical properties.