Nacre (also called mother-of-pearl) is known to have a delicate balance of stiffness, strength, and toughness, which originates from its ‘brick-and-mortar’ structure. In this study, nacre-like structures are fabricated using a high-resolution, multi-material 3D printer, where two different polyurethane acrylates (one that is hard and another that is soft) are used to represent the tablets and matrix. Six nacre-like structures are designed and fabricated to explore the influence of geometric parameters on the mechanical behaviors. Quasi-static in-plane compression tests and simulations are carried out to explore the failure mechanism of the nacre-like structures. The results show that the quasi-static compression responses of nacre-like structures have four stages: elastic, plateau, fragmentation, and densification. It is found that tuning the nacre architecture can optimize the mechanical performance of the specimen, including the peak load, ductility and stress reduction behavior et al. As the results of the numerical model show good agreement with the stress–strain response observed in the experiments, the model is applied to further investigate the strain distributions of the nacre-like structures. The patterns of the strain distribution suggest that synergistic deformation is the key toughening mechanism for the nacre-like structures.