To address the problem that how straight-chain and branched solvent affect the solubility of active pharmaceutical ingredient, in this work, the molar fraction solubility of form I of probucol in five alcohols with straight and branched alcohols was determined by gravimetric method ranging from 278.15 to 323.15 K. The results showed that the equilibrium solubility of probucol is temperature-dependent and increased monotonically with temperature. More importantly, our findings show that the solubility of probucol rose as the number of straight-chain carbons grew and that it is more soluble in straight-chain alcohols than in branched alcohols with an equivalent carbon count. Furthermore, we conclude that the solubility of probucol in various solvents in straight-chain alcohols is co-dominated by solvent polarity and cohesive energy density, while in branched alcohols, the solubility of PBL is co-dominated by steric hindrance and temperature. Then, three thermodynamic models were employed to correlate the experimental solubility data and derive the dissolution thermodynamic properties of PBL. Our results indicated that except for ethanol, the dissolution process of PBL in other alcohols is enthalpy-driven and spontaneous, while in the case of ethanol, the dissolution of PBL transforms from entropy-driven to enthalpy-driven.