Carbamazepine (CBZ), a Biopharmaceutics Classification System (BCS) class II drug, is widely-used as a first line antiepileptic drug. Numbers of cocrystals have reported to regulate its poor solubility. However, the solubility behaviors are rarely discussed on theoretical calculations and phase solubility diagrams. In this study, two new drug-drug cocrystals (DDC) of CBZ with emodin (EMO, 1: 1) and paeonol (PAE, 1: 1) as conformers, which offer the advantages of synergetic therapy and patient compliance are reported for the first time. The solubilities in water and in pH = 1.2, 6.8 buffer solutions, demonstrating that the rank order is as follows: CBZ-PAE > CBZ > CBZ-EMO. CBZ-PAE presents the biggest solubility at 0.563 ± 0.003 mmoL/L of in water among all the investigated samples. The solubilities of all the starting materials and cocrystals in six pure organic solvents such as methanol, ethanol, 2-propanol, acetone, acetonitrile, ethyl acetate were investigated to discuss the phase solubility diagrams. The results indicate that experimental solubilities are consistent with the theoretical solubilities on consideration of solubility product (Ksp) and solution binding constant (K11) together. The enthalpy differences between cocrystal and its coformer are calculated through the Perdew-Burke-Ernzerhof (PBE) functional with the projector augmented wave (PAW) pseudopotentials. CBZ-EMO presents the lowest enthalpy (−0.38 kcal/mol) with a highly unfavorable solvation energy (2.42 kcal/mol), resulting in unfavorable in an aqueous environment. Overall, the phase solubility diagrams and theoretical calculations support the solubility regulations on DDCs of CBZ. © 2021 Elsevier B.V.