DFT calculations of ground state of the Trans and Cis conformations of praziquantel hemihydrate and its derivatives were performed by using hybrid functional BPV86 with 6–31G (d, p) as basis set. A detailed vibrational spectral analysis was performed, and potential energy distribution (PED) was used to propose assignments for the observed bands. The electric dipole moment (μ), polarizability (α), and molecular first hyperpolarizability (β) were characterized in these compounds. The HOMO–LUMO energy gaps and the global chemical reactivity descriptors were computed by BPV86 using 6–31G (d, p), while the excitation energies have determined by time-dependent DFT (TDDFT). The stability and charge delocalization were studied by natural bond orbital analysis. Topological analyses including atom in molecule (AIM), reduced density gradient (RDG), natural bonding orbital (NBO), and molecular electrostatic potential (MEP) have used to compute intermolecular interactions and in particular hydrogen bonds. The obtained first-order hyperpolarizabilities in the range of 0.6316 × 10−30–4.3460 × 10−30 esu revealed that the praziquantel hemihydrate and its derivatives have better NLO properties. The low-energy gap of 4.3081 eV generates an intramolecular charge transfer, leading to the enhancement of the NLO activity in these compounds.