The present study investigates the release mechanism of benznidazole (BNZ) in solid dispersions with polyethylene glycol 6000 (PEG 6000) and polyvinylpirrolydone K-30 (PVP K-30), with a view to observing the increase in solubility of BNZ in water in the presence of these two hydrophilic polymers. The interaction of BNZ with the polymers was evaluated using scanning electron microscopy, Fourier-transformation infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, and in vitro dissolution tests, and a theoretical study of molecular modeling was also carried out. The drug-polymer interaction was studied trough molecular modeling, using density functional theory with the B3LYP exchange correlation function. The corrected interaction energies were calculated to be -20.9 kJ/mol with PVP and -6.6 kJ/mol with PEG. The experimental and theoretical results indicate that a powerful interaction occurred between BNZ and the polymers, which was especially strong in the case of PVP, and that this interaction contributed to improvement of BNZ solubility.