The invention provides a preparation method of ceftiofur hydrochloride, which comprises the following steps: step 1, preparation of a ceftiofur hydrochloride crude product: adding 7-ACF into an organic solvent, dropwise adding organic alkali for dissolving, then adding AE active ester, carrying out heat preservation reaction, after the reaction is finished, adding hydrochloric acid to adjust the pH, and filtering to obtain the ceftiofur hydrochloride crude product; and 2, refining the ceftiofur hydrochloride, adding the crude ceftiofur hydrochloride product obtained in the step 1 into water, adding alkali to adjust the pH value, dissolving, filtering by adding activated carbon, adding hydrochloric acid to adjust the pH value, dropwise adding an organic solvent into the filtrate, crystallizing, filtering and drying to obtain a white product, namely the ceftiofur hydrochloride. In the preparation process, the solvent amount is small, the solvent can be recycled and reused, waste water is little, the method is more environmentally friendly, the purity of the product ceftiofur hydrochloride reaches 99.0% or above, the reaction yield is high, and the appearance color is good; the method is simple in preparation process, short in production period, high in product purity, high in yield, economical and environment-friendly.