Harmine (HAM) is a natural product with neuroprotective and antitumor activity. Its poor aqueous solubility is the major factor limiting its clinical application. In this work, seven new organic acid salts of HAM were prepared and systematically characterized. Their single crystals were obtained, and the structures were identified by a single-crystal X-ray diffractometer. The corresponding solubilities in water were determined in the temperature range of 20−35 °C by the HPLC method. All HAM salts showed significantly improved powder solubility profiles compared with the free base. The relationship between the aqueous solubility and the single-crystal structures of HAM organic salts was explored from several perspectives, including the basic properties of acidic counterions, the intermolecular force in crystals (type of lattice force, cohesive energy density, and lattice energy), the factors affecting the dissolution process (hydration energy and sublimation energy), and the external environmental factors (chemical hardness). The aqueous solubility of different HAM salts was dependent on the type of charge assistant hydrogen bonds; that is, the salts withbonds exhibited better solubility than the other salts with N + −H•••O − hydrogen bonds. In addition, the results revealed that HAM salts with higher acidic counterion intrinsic solubility (S ACID ) showed smaller cohesive energy density of the crystal; the larger the absolute value of hydration energy (ΔG hyd 0 ), the greater the chemical hardness (η) of acidic anions in the crystal and ultimately the better the equilibrium solubility in water. The rank order of the linear fitting accuracy of these four parameters regarding solubility was as follows: Δη > CED > ΔG hyd 0 . The solubility of HAM organic acidic salts is associated with several factors, even though the chemical hardness seems to play a central role.