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Trimethoprim (TMP) is a commonly used BCS class II antibiotic, the water solubility of which needs to be improved to overcome the limitations in oral administration. Herein, we combined TMP with pharmaceutically acceptable coformers (CCFs) by co-crystallization method and reported five new salts (two solvated salts and three unsolvated salts) of TMP. The crystal structures of the salts were determined by single-crystal X-ray diffraction. The supramolecular interactions in the crystal structures were theoretically investigated via molecular electrostatic potential surface (MEPs), Hirshfeld surface, and atoms-in-molecules (AIM) analyses of TMP and CCFs. The properties of the salts were experimentally characterized by using TGA, DSC, hot stage microscopy, and Fourier transform infrared (FTIR) spectroscopy. Furthermore, the equilibrium solubility and intrinsic dissolution rate (IDR) of the salts were determined and compared to that of bare TMP in buffers of pH 1.2 and 6.8. It was found that the equilibrium solubility and IDR of TMP–GA–2M (GA: gallic acid; M: methanol), TMP–SYA–0.16H (SYA: syringic acid; H: H2O), and TMP–OA (OA: orotic acid) dramatically increased in both buffers. The antibacterial activity measurement of these three salts against Escherichia coli revealed that the bacteriostasis rate of the three salts all increased by more than 40% and the minimum inhibitory concentrations (MICs) of salts all decreased compared to that of TMP. There may be drug synergism between the API and the CCF. Based on food safety considerations, TMP–SYA–0.16H and TMP–OA will have more potential prospects in further application of TMP. [ABSTRACT FROM AUTHOR]