The invention discloses an application of an insect small-molecule active substance in preparing an antiatherosclerotic medicine. The insect small-molecule active substance of the invention is prepared by the method comprising the following steps: (1) feeding adult flies, attracting the adult flies to spawn, feeding larvae with feed, and removing feed residues; (2) carrying out cold and hot stimulus induction on the larvae; and (3) after inducing for 48h, collecting the larvae, cleaning, disinfecting, breaking polypide cells, homogenizing at high speed, centrifugating, separating supernate, ultrafiltering, and obtaining the insect small-molecule active substance of which the molecular weight is less than 30KD after the filtrate is subject to freeze drying. The purely natural insect small-molecule active substance of the invention can effectively reduce the serum inflammatory factors and adjust the blood fat, promotes cholesterol efflux of macrophage, has an oxidation-resisting efficacy, and can be applied in a plurality of the fields of medical treatment, feed processing, food industry and the like.