Praziquantel (PZQ), a broad-spectrum anthelmintic drug and the first-line treatment for schistosomiasis, is listed on the WHO Model List of Essential Medicines. Although highly effective, PZQ is characterized by poor aqueous solubility, motivating crystal engineering strategies to modulate its physicochemical properties. Here, we employed mechanochemical crystal engineering of PZQ with 5-hydroxyisophthalic acid (5HIP), benzene-1,3,5-tricarboxylic acid (TRI), and trans,trans-muconic acid (MUC) as coformers selected to provide diverse hydrogen-bonding patterns and supramolecular architectures. This approach yielded eight novel pharmaceutical solid forms, comprising cocrystals and cocrystal solvates. Mechanochemical synthesis enabled rapid and reproducible access to phase-pure multicomponent systems using limited amounts of solvents, while solution-based crystallization yielded single crystals for X-ray diffraction. Structural analysis revealed robust supramolecular synthons dominated by O-H···O hydrogen bonding. Thermal analysis and aqueous solubility measurements revealed distinct physicochemical properties among the multicomponent systems, related to their supramolecular organization. Cocrystallization also modulated the biological activity profile of PZQ, with selected systems exhibiting distinct antimicrobial effects. Overall, this work demonstrates that mechanochemical crystal engineering provides a rational approach to designing multicomponent pharmaceutical solid forms and establishes structure-property relationships linking crystal packing with the physicochemical and biological properties of PZQ.