The solubility of (+)-usnic acid ((+)-UA) in ten pure solvents and five binary mixed solvents was determined over the temperature range of 283.15–323.15 K. The experimental data for pure solvents were correlated using the modified Apelblat, λh, Wilson and NRTL models, while the General Solubility model (GSM) and the Jouyban-Acree (JA) model were additionally applied to binary solvent systems. The solubility of (+)-UA increased monotonically with temperature and the mass fraction of good solvent, and the Wilson model provided the most accurate overall correlation. The KAT-LSER model was then employed to evaluate solvent effects. The analysis showed that solvent-solvent cohesive energy density significantly hindered the dissolution process, while dipolarity/polarizability exerted only a moderate influence. Molecular simulations, including intramolecular hydrogen-bond analysis and molecular electrostatic potential (MEP) surfaces, were carried out to explore hydrogen-bond interactions among the enol-keto tautomers of (+)-UA. Strong intramolecular hydrogen bonding was found to favor compact conformations and to reduce solvent accessibility, whereas tautomers with more exposed polar regions exhibited enhanced solvation capability. Free-energy calculations further suggested that the dissolution behavior reflects a balance between intramolecular stabilization and solute-solvent interactions. In addition, thermodynamic analysis based on activity coefficients derived from the Wilson model indicated that both the mixing and dissolution processes were spontaneous and mainly driven by entropy. Keywords: (+)-Usnic acid; Solubility; Molecular simulation; Thermodynamic analysis.