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Praziquantel (PZQ) is one of the most widespread anthelmintic drugs. However, the frequent insufficient application of PZQ after oral administration is associated with its low solubility, penetration rate, and bioavailability. In the present study, the permeation of PZQ through a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membrane was investigated to probe glycyrrhizin-assisted transport. Glycyrrhizin (or glycyrrhizic acid, GA), a natural saponin, shows the ability to enhance the therapeutic activity of various drugs when it is used as a drug delivery system. However, the molecular mechanism of this effect is still under debate. In the present study, the transport rate was measured experimentally by a parallel artificial membrane permeation assay (PAMPA) and molecular dynamics (MD) simulation with DOPC lipid bilayers. The formation of the noncovalent supramolecular complex of PZQ with disodium salt of GA (Na2GA) in an aqueous solution was proved by the NMR relaxation technique. PAMPA experiments show a strong increase in the amount of the penetrating praziquantel molecules in comparison with a saturated aqueous solution of pure drug used as a control. MD simulation of PZQ penetration through the bilayer demonstrates an increase in permeability into the membrane in the presence of a glycyrrhizin molecule. A decrease in the free energy barrier in the middle of the lipid bilayer was obtained, associated with the hydrogen bond between PZQ and GA. Also, GA reduces the local bilayer surface resistance to penetration of PZQ by rearranging the surface lipid headgroups. This study clarifies the mechanism of increasing the drug’s bioavailability in the presence of glycyrrhizin.