Nanoindentation tests and finite element analysis that considers elastic-mesoplastic deformation for single crystals were used to investigate the mechanical properties of CaF2 under spherical indentation. The goal was to gain a better understanding of microfractures and crystalline anisotropy and their effect on the surface quality of CaF2 during manufacturing. In this analysis, indentations of the three main crystallographic planes (100), (110), and (111) were studied and compared to examine the effects of crystalline anisotropy on the load–displacement curves, surface profiles, contact radius, spherical hardness, stress distributions, and cleavage at two stages, namely at the maximum indentation load and after the load had been removed. Our model results were compared with experimental observation of surface microroughness, subsurface damage, and material removal rate in grinding of CaF2.