This research deals with the determination of solubility, Hansen solubility parameters, dissolution properties, enthalpy-entropy compensation, and computational modeling of a naturally-derived bioactive compound trans-resveratrol (TRV) in water, methanol, ethanol, n-propanol, n-butanol, propylene glycol (PG), and various PG + water mixtures. The solubility of TRV in six different mono-solvents and various PG + water mixtures was determined at 298.2-318.2 K and 0.1 MPa. The measured experimental solubility values of TRV were regressed using six different computational/theoretical models, including van't Hoff, Apelblat, Buchowski-Ksiazczak λh, Yalkowsly-Roseman, Jouyban-Acree, and van't Hoff-Jouyban-Acree models, with average uncertainties of less than 3.0%. The maxima of TRV solubility in mole fraction was obtained in neat PG (2.62 × 10-2) at 318.2 K. However, the minima of TRV solubility in the mole fraction was recorded in neat water (3.12 × 10-6) at 298.2 K. Thermodynamic calculation of TRV dissolution properties suggested an endothermic and entropy-driven dissolution of TRV in all studied mono-solvents and various PG + water mixtures. Solvation behavior evaluation indicated an enthalpy-driven mechanism as the main mechanism for TRV solvation. Based on these data and observations, PG has been chosen as the best mono-solvent for TRV solubilization.