The invention belongs to the technical field of organic acid ester cellulose preparation, in particular relates to a production method of spherical cellulose acetate butyrate, and solves the technical problem of low product yield. The production method comprises the following steps: a, treating velvet wood pulp or cellulose acetate grade refined cotton by acetic acid; b, mixing butyric anhydride, acetic anhydride and concentrated sulfuric acid, cooling to obtain cooled mixed liquid, adding the treated velvet wood pulp or cellulose acetate grade refined cotton into the cooled mixed liquid, and adding a solvent for acylation; c, adding hydrolysis liquid into acylation reaction liquid for hydrolysis, and neutralizing; d, precipitating, hardening, performing solid-liquid separation, washing, stewing, and drying to obtain a spherical cellulose acetate butyrate product. According to the method provided by the invention, the apparent viscosity of materials in reaction liquid can be effectively reduced, the mixing effect of the materials can be improved, the reaction performance of the materials can be improved, and the reaction yield of the materials can be increased.