<p>The solubility of 3,4,5-Trimethoxyphenylacetonitrile (TMB) was measured by employing a static gravimetric method in twelve pure solvents (methanol, ethanol, <i>n</i>-propanol, <i>iso</i>-propanol, <i>n</i>-butanol, 2-butanol, <i>n</i>-hexane, cyclohexane, <i>n</i>-heptane, ethyl acetate, <i>iso</i>-propyl acetate, <i>N,N’</i>-dimethyl formamide (DMF)) with the temperature ranging from 283.15 to 323.15&#xa0;K under the atmospheric pressure. The experimental results demonstrated that the mole fraction solubility of TMB increased with the increasing temperature in all systems, and the solubility of TMB is the highest in DMF and lowest in n-heptane. The experimental solubility of TMB was fitted using the modified Apelblat, Wilson, Yaws, and <i>λh</i> models. And the experimental data were agreed well with these models. Furthermore, the results show that the best fitting model was the modified Apelblat model with an average relative deviation of less than 1%. The intermolecular forces between solute and solvent were evaluated by the cohesive energy density obtained by molecular dynamics simulation, and the solubility and compatibility of solute and solvent were predicted. The analysis of Hansen solubility parameters was performed to investigate the similarities between solvents and TMB, thereby improving our understanding of their dissolution behaviors. The thermodynamic properties of the dissolution process are also calculated using the Wilson model. The results show that the dissolution of TMB is an endothermic process driven by enthalpy.</p>