The invention belongs to the technical field of self-cleaning coating products, and particularly relates to a preparation method of a self-cleaning coating based on a liquid-like polymer grafted surface, which comprises the following steps: (1) forming a liquid-like film on the surface of a substrate to change the substrate into a modified substrate: covalently grafting methoxy or hydroxyl-terminated PDMS on the substrate through chemical vapor deposition or liquid phase reaction; (2) washing off redundant PDMS by using methylbenzene and drying the substrate; (3) testing the anti-pollution performance of the modified substrate on biological substances, bacteria, staphylococcus aureus and mammalian cells; (4) testing the adhesion resistance of the modified substrate to the living liquid; and (5) carrying out induction learning to obtain reaction conditions and test conditions required by corresponding materials. The surface of the self-cleaning coating has high lubricating capacity, lasting biological adhesion resistance and high wear resistance; besides, the PDMS is a fluorine-free polymer, so that fluorine pollution cannot be caused in multiple applications, and the method is widely applied to preparation of medical implants and biological equipment with anti-adhesion performance and domestic liquid containers.