The solubility and thermodynamic characteristics of phenol red were determined by the static equilibrium method combined with HPLC. The equilibrium solubility of phenol red in 12 monosolvents (methanol, ethanol, npropanol, isopropanol, n-butanol, isobutanol, acetonitrile, methyl acetate, ethyl acetate, DMF, water, and acetone) was measured at a temperature range of 278.15−323.15 K and a constant pressure of 101.1 kPa. The results showed that in the experimental temperature range, the solubility of phenol red is positively correlated with the temperature and reached the maximum and minimum values in DMF and isobutanol. Ethanol, acetonitrile, and water were randomly selected to form three groups of binary mixed solvents, the monosolvent with high solubility is used as the cosolvent in the binary mixed solvent, and the solubility data were measured under the same experimental conditions. Interestingly, in all binary mixed solvents, the solubility data of phenol red showed a trend of first increasing and then decreasing with the increase of the proportion of cosolvent. The Buchowski−Ksiazaczak λh model and Apelblat model were used to fit the solubility data of phenol red in monosolvent, and the average root mean square deviation (RMSD) values are 3.8775 × 10 −2 and 4.6592 × 10 −3 . The Jouyban−Acree model, CNIBS/R-K model, and Sun model were used to fit the solubility data of phenol red in binary mixed solvent, and the average RMSD values were 9.4265 × 10 −6 , 5.1215 × 10 −6 , and 9.4265 × 10 −6 . Furthermore, the solvation of phenol red was investigated by the KAT-LSER model. The results showed that the acidity of the hydrogen bond had a significant effect on the solubility, and the contribution rate was 35.5%.