The invention discloses a polysubstituted 1,2,4-oxadiazole-5-imine derivative and a synthesis method thereof, and belongs to the field of organic matter synthesis, wherein the method comprises the steps: adding a solvent into a container loaded with substituted nitrone and a substituted carbodiimide compound, stirring at the reaction temperature of 25 DEG C-100 DEG C, washing with water or a saturated salt solution after the reaction is finished, then extracting with an organic solvent, drying, carrying out reduced pressure distillation and concentration to remove the solvent, and carrying outcolumn chromatography separation on the crude product to obtain the target product 1,2,4-oxadiazole-5-imine compound. The method has the advantages of no transition metal catalyst, cheap and accessible raw materials, wide reaction substrate adaptability, mild reaction conditions, favorable regioselectivity, high yield, environment friendliness and the like, and has favorable industrial application prospects.