Mechanochemical activation using several different co-grinding additives was applied as a green chemistry approach to improve physiochemical and biopharmaceutical properties of praziquantel (PZQ). Liquid assisted grinding with an equimolar amount of citric acid (CA), malic acid (MA), salicylic acid (SA) and tartaric acid (TA) gained in cocrystal formation, which all showed pH-dependent solubility and dissolution rate. However, the most soluble cocrystal of PZQ with MA was chemically unstable, as seen during the stability testing. Equimolar cyclodextrin complexes prepared by neat grinding with amorphous hydroxypropyl-β-cyclodextrin (HPβCD) and randomly methylated β-cyclodextrin (MEβCD) showed the highest improvement in drug solubility and the dissolution rate, but only PZQ/HPβCD product presented an acceptable chemical and photostability profile. A combined approach, by co-grinding the drug with both MA and HPβCD in equimolar ratio, also gave highly soluble amorphous product which again was chemical instable and therefore not suitable for the pharmaceutical use. Studies on Caco-2 monolayer confirmed the biocompatibility of PZQ/HPβCD complex and showed that complexation did not adversely affect the intrinsically high PZQ permeability (Papp(PZQ) = (3.72 ± 0.33) × 10−5 cm s−1 and Papp(PZQ/HPβCD) = (3.65 ± 0.21) × 10−5 cm s−1; p > 0.05). All this confirmed that the co-grinding with the proper additive is as a promising strategy to improve biopharmaceutical properties of the drug.