The invention provides a preparation method of a hyaluronic acid graft polymer vesicle, and belongs to the technical field of high molecular materials and natural macromolecule materials. The preparation method comprises the following steps: introducing an L-phenylalanine ethylester unit on a hyaluronic acid side chain through amidation, and endowing the hyaluronic acid with certain amphipathicity. The polymer vesicle is formed through self-assembly according to a solvent exchange method. The obtained polymer vesicle has excellent biocompatibility and biodegradability, and has a good application prospect in the fields such as bio-coatings, particle emulsifiers, bioactive molecule load and drug release.