Clear understanding of the relationships among crystal structure, mechanical properties, and tableting performance is of enormous importance for successful development of tablet products. This study was aimed at systematically examining such relationships using four salts of diphenhydramine (DPH), a first-generation H-receptor antagonist, i.e., hydrochloride (DPH-HCl), citrate (DPH-Cit), saccharinate (DPH-Sac), and acesulfamate (DPH-Acs). The conformation and intermolecular interactions of DPH as well as crystal packing in the four salts were considerably different. Both the energy framework and visualization of the crystal structure revealed the greatest plasticity of DPH-Acs, which was characterized by drastically different intermolecular interactions in orthogonal directions. This was consistent with its facile bending behavior and the lowest hardness. The most plastic DPH-Acs also exhibited the best tabletability, which was accompanied by greater compressibility and compactibility as well as smaller elastic recovery than the other three salts. Among the three hard brittle DPH salts, higher crystal hardness corresponded to poorer tabletability. This work demonstrates the technological feasibility of understanding or even predicting tableting performance based on crystal structures and mechanical properties.