Solubility data of naphazoline nitrate in four binary solvents namely “methanol/2-methoxyethanol/ethylene glycol/N,N-dimethylformamide plus isopropanol” was determined in temperature range of (278.15 ∼ 323.15) K under 0.1 MPa. The laser monitoring method was employed during solubility determination process, and the composition of positive solvent was ranged from 0 to 1.0 with the mass fraction interval about 0.1. Solubility values showed an obvious growth trend with the increase of temperature, at the same time, it also had positive correlation with incremental mass fraction of positive solvent. The maximum as well as minimum values of naphazoline nitrate solubility data were obtained in neat N,N-dimethylformamide at 323.15 K (0.1855) and isopropanol at 278.15 K (5.766e−4). Besides, solubility modeling was realized by four activity coefficient models namely “Margules, Wilson, NRTL, UNIQUAC model”, and four selected models could provide good fitting effect among solubility data, solvent composition and experimental temperature. Corresponding root mean square deviation and average relative deviation between experimental and computed solubility data were not more than 2.759‰ and 6.727%, respectively. Moreover, Hansen solubility parameter were applied for discussing the miscibility between NPZN and selected solvents. Furthermore, thermodynamic properties, i.e. Gibbs free energy, entropy and enthalpy, for dissolution process and mixing process, were evaluated by UNIQUAC model. Results showed that dissolution processes were spontaneous and entropically driven, at the same time, most of mixing processes excluding naphazoline nitrate in isopropanol and methanol were spontaneous, exothermic and entropically driven.