Solubility values of guanidine hydrochloride (GuHCl) in 11 different neat solvents namely “2-methoxyethanol, ethanol, N,N-dimethylformamide (DMF), n-propanol, 2-propoxyethanol, methanol, 2-ethoxyethanol, isopropanol, N-methyl pyrrolidone (NMP), 2-butoxyethanol and N,N-dimethylacetamide (DMAC)” were determined experimentally using a laser monitoring method under “p = 0.1 MPa”. The investigated temperature was set from 278.15 K to 323.15 K. The experimental results indicated that solubility of GuHCl increased with the increasing temperature. At 298.15 K, solubility of GuHCl was ranked as: DMF (0.4017) > DMAC (0.3400) > 2-methoxyethanol (0.3330) > 2-ethoxyethanol (0.2963) > 2-propoxyethanol (0.2158) > methanol (0.2017) > NMP (0.1704) > 2-butoxyethanol (0.1531) > ethanol (0.1174) > isopropanol (0.08857) > n-propanol (0.06604). Moreover, the effect of interactions between GuHCl and solvent molecules on solubility sequence was analyzed by solvation free energy or radial distribution function. The results acquired from molecular simulation analysis indicated that the whole dissolution behavior of GuHCl in investigated solvents was a complicated process. Furthermore, the recorded solubility of GuHCl was correlated and computed with the Two-Suffix Margules, nonrandom two-liquids (NRTL), Wilson and Apelblat model, which the Apelblat equation performed the best correlate results than another three models. Finally, thermodynamic mixing and dissolution properties were calculated on the basis of Wilson model, and the mixing and dissolution process were both found to be entropy-driven and spontaneous.