The solubility of 5-chloro-2-nitroaniline in twelve mono-solvents (water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, acetone, 2-butanone, acetonitrile, methyl acetate, ethyl acetate) at 101.2 kPa (T = 283.15 ∼ 323.15 K) was investigated by experimental determination and molecular simulation. The static gravimetric tests showed that the solubility of 5-chloro-2-nitroaniline increased with the increase of absolute temperature, in the following order: 2-butanone > acetone > methyl acetate > ethyl acetate > acetonitrile > n-butanol > n-propanol > ethanol > isopropanol > isobutanol > methanol > water. The modified Apelblat, Wilson, NRTL, UNIQUAC and Margules models were used to correlate the experimental data, and the fitting results of the five models were satisfactory. By comparing the average ARD and RMSD values of the five models, the correlation results of the modified Apelblat model were the best. Hirshfrld surface analysis (HS) and molecular electrostatic potential surface (MEPS) were used to determine the internal interaction of 5-chloro-2-nitroaniline solution. The Hansen solubility parameters (HSPs) was utilized to assess the solvents’ capability and to elucidate its ability to dissolve 5-chloro-2-nitroaniline. Furthermore, mixing thermodynamic characteristics of 5-chloro-2-nitroaniline in selected solvents were calculated by the NRTL model, which revealed that the mixing process was spontaneous and entropy-driven. These experimental results could be utilized for the purification, crystallization, and industrial applications of 5-chloro-2-nitroaniline as well as similar substances.