Vortioxetine, a novel antidepressant for the treatment of major depressive disorder, has a low water solubility, and the feature limits its bioavailability and efficacy. The aim of this paper is to improve the water solubility of vortioxetine by salt formation. In this paper, two new salts of the multimodal antidepressant vortioxetine with 2-picolinic acid and isonicotinic acid have been successfully prepared by the slow solvent evaporation method, and their crystal structures have been determined from single-crystal X-ray diffraction data. Structural analyses have shown the two salts have the similar N-H?O hydrogen bond base frame. Hirshfeld surface analysis have been carried out to gain additional insight into the differences of intermolecular interaction between the salt structures. The two vortioxetine salts was characterized and analyzed using infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction. Compared with vortioxetine, two salts both showed the better thermal stability. The two salts both showed enhancement in solubility compared with vortioxetine. Overall, the results showed salt formation of vortioxetine with 2-picolinic acid and isonicotinic acid has the ability to change its physicochemical properties.