The purpose of this work was to measure the equilibrium solubility of naphazoline hydrochloride (NPZ) in different mono-solvents ranged from 278.15 K to 323.15 K by a laser monitoring method. In this research, N-methyl pyrrolidone (NMP), n-propanol, 2-butoxyethanol, ethanol, 2-methoxyethanol, N,N-dimethylformamide (DMF), methanol, ethylene glycol (EG), isopropanol, 2-propoxyethanol and 2-ethoxyethanol were selected as the experimental solvents. The results indicated that solubility data of NPZ in 11 neat solvents increased with the increase of temperature. At 298.15 K, the maximum solubility was observed in EG (5.028e-2), followed by 2-methoxyethanol (2.460e-2), methanol (2.429e-2), 2-ethoxyethanol (7.788e-3), ethanol (6.391e-3), 2-propoxyethanol (4.216e-3), n-propanol (3.373e-3), 2-butoxyethanol (3.144e-3), DMF (2.348e-3), NMP (2.002e-3) and isopropanol (1.689e-3). Moreover, the solvent polarity, radial distribution function (RDF) and solvent effect (KAT-LSER model) were implemented to investigate the impact of solute-solvent interactions on solubility behavior of NPZ. The results demonstrated that the whole dissolution behavior of NPZ in organic solvents was a complicated process, and the solvent-solute interactions were associated with hydrogen bond acidity and dipolarity/polarizability of solvent. Besides, the NRTL-SAC, Two-Suffix Margules, Wilson, NRTL and UNIQUAC models were employed to fit experimental solubility data. Deviation analysis revealed that the Wilson model reflected the best agreement between measured data and calculated values with the minimum mean values of average relative deviation (100ARD, 0.9144) and root-mean square deviation (104RMSD, 1.062). Furthermore, the positive entropy changes and negative values of Gibbs energy changes showed that mixing and dissolution process of NPZ in 11 neat solvents were confirmed to entropy-driven and spontaneous.