Nacre's superior mechanical properties and failure behavior are strongly orientation-dependent due to its brick-and-mortar microstructure. In this work, the anisotropic microscopic deformation and the resulting macroscopic mechanical properties are evaluated under different loading conditions. Our in situ transmission electron microscopy deformation experiments and finite element simulations reveal that nacre possesses enhanced indentation resistance along the direction normal to the tablets through delocalization of indentation-induced deformation by taking advantage of its layered structure.