Chlortetracycline hydrochloride (CTC) has been reported as having low aqueous solubility, leading to a limitation in its administration in treatments. This study demonstrated a strategy to enhance the supersaturated solubility of CTC by amorphous solid dispersion (SD). CTC-SDs were prepared with hydrophilic polymers, polyvinylpyrrolidone (PVP) and copovidone using various preparation methods: water bath evaporation, speed vacuum evaporation, and spray drying. Physicochemical properties and antimicrobial susceptibility of CTC-SDs were evaluated. It was found that CTC-SDs could be successfully prepared by spray drying with PVP-K17 and PVP-K30 as carriers at drug/polymer weight ratios of 1:4 and 1:5. They exhibited more than a ten-fold increase in CTC solubility. CTC-SDs could be solubilized at such high concentrations for up to 6 h without recrystallization. PXRD and SEM results demonstrated the transformation of the crystalline drug to an amorphous nature. FTIR spectra suggested the occurrence of intermolecular interactions. A significant increment of dissolution of the CTC-SD samples was achieved compared to the crystalline drug. Further, in comparison with CTC, CTC-SDs were equally active againstand , indicating that the microbiological effectiveness of the CTC-SDs was maintained. This study suggests that amorphous SD is a promising method for improving the solubility of CTC.