The invention discloses a water-soluble florfenicol clathrate with high bioavailability. The water-soluble florfenicol clathrate is prepared from the following components in parts by weight: 5-15 parts of florfenicol or pharmaceutically acceptable salt of florfenicol, 20-60 parts of a florfenicol adsorption carrier, 1-2 parts of an absorption promoter, and 10-30 parts of a florfenicol cosolvent. For the florfenicol clathrate provided by the invention, the solubility of florfenicol is effectively improved, the bioavailability of florfenicol is improved, the hemolysis property of the medicine is alleviated, the release rate of the medicine is controlled, and the bad smell is masked. The preparation method provided by the invention comprises the following steps: firstly, mixing the florfenicol adsorption carrier, the absorption promoter and the florfenicol cosolvent, adding with florfenicol or the pharmaceutically acceptable salt of florfenicol under the water bath water control condition, carrying out stirring, carrying out heat preservation, and carrying out drying, thus obtaining the florfenicol clathrate. The technological operation is simple, the abundant time and manpower are saved, and during the preparation process, no organic solvents are used, so that the preparation method is safe and reliable and is free of pollution, and the process is simple and easy to realize.