The invention discloses a preparation method of a compound cortisone acetate. The method takes a compound 4-pregnen-11(alpha),17(alpha)-alcohol-3,20-diketone (I) as a raw material and a mixed solution of chromic anhydride, sulfuric acid and water as an oxidation reagent, and comprises the following steps of: oxidizing the eleventh site to obtain a compound 4-pregnen-17(alpha)-alcohol-3,11,20-triketone (II); then iodizing the twenty-first site to obtain a compound 4-pregnen-21-iodine-17(alpha)-alcohol-3,11,20-triketone (III); and finally performing a replacement reaction to enable the compound 4-pregnen-21-iodine-17(alpha)-alcohol-3,11,20-triketone (III) to react with potassium acetate in a replacement reaction solvent to obtain a compound 4-pregnen-21-iodine-17(alpha),21-diol-3,11,20-triketone-21-acetate (IV), namely cortisone acetate. Through the invention, the dangerous operation of bromination and hydrogenation reaction can be avoided, the product yield can be improved, the process cost can be lowered, and the production is more economical, safer and more environment-friendly, thus the method is more suitable for industrial production.