In this study, a statistical experimental design was used to evaluate the effects of manufacturing factors and material properties on the mechanical performances of microcrystalline cellulose (MCC) products for the purpose of optimizing mechanical performances and reducing source variations affecting tablet strength of MCC. Results demonstrated that only fracture toughness and sensitivity to compaction speed among mechanical performances were affected by the manufacturing factors; however, the use of manufacturing factors to predict the mechanical performances was poor. On the other hand, the critical stress intensity factor, fracture toughness, and sensitivity to compaction speed can be quantitatively predicted by material properties examined in this study. Meanwhile, the cohesive energy density (CED), degree of crystallinity, crystallinity index, and shape index may serve as important material properties for controlling the mechanical performances of MCC. In conclusion, although the MCC products with high fracture toughness and low sensitivity to compaction speed could be optimally obtained, it was not possible to manipulate manufacturing factors to directly control the exact mechanical performances of MCC products. Instead, material properties of MCC products might potentially be used to precisely predict their mechanical performances. The influence of source variations of MCC products on the strength of tablets might be reduced by regulation of their CED, degree of crystallinity, crystallinity index, and shape index.