The solubility of griseofulvin in buffer solutions (pH 2.0 and 7.4), 1-octanol and hexane was measured in the temperature range 293.15–313.15 K by the shake flask method. It was found that griseofulvin is poorly soluble in aqueous buffer solutions (x≤8.63·10−7), while the best solubility is observed in 1-octanol (x≤6.56·10−4). The solubility evaluation in different solvents with the help of Hansen solubility parameters showed the consistency with the experimental data. The solubility was revealed to significantly depend on the dispersion interactions and polar bonds. The dissolution and solvation thermodynamic functions of the drug were calculated. The Gibbs energy and enthalpy of drug dissolution in aqueous and organic solvents are positive, which characterizes the dissolution process as hindered and endothermic. The van’t Hoff and Apelblat equations gave good correlations when used for modeling the experimental solubility results. Based on the data on the solubility and thermophysical parameters of the compound, the temperature dependences of the activity coefficients were determined and the excess thermodynamic functions of dissolution were calculated. Positive deviation from ideality was observed in all the solvent-solute systems studied. The partition coefficients of the drug in the 1-octanol/buffer pH 7.4 system were obtained and the transfer thermodynamic functions were derived. It was established that the drug distribution from the aqueous solution to the octanol phase was thermodynamically favorable and endothermic.