The invention belongs to the technical field of organic synthesis and specifically discloses a preparation method of an acyl-substituted pyrazine compound. The preparation method comprises the following steps: (1) adding a silver catalyst, an oxidizing agent, a pyrazine compound and a benzoyl formic acid compound into a solvent for a reaction and cooling to room temperature, so as to obtain reaction liquid; (2) separating and purifying the reaction liquid obtained in step (1), so as to obtain a product. In the preparation method, the corresponding acyl-substituted pyrazine compound is generated by a direct coupling reaction in air by taking silver salt as the catalyst and taking the pyrazine compound and the benzoyl formic acid compound that are low in cost and are easily available as rawmaterials, and the product can serve as a drug intermediate and a flavor precursor compound with biological activity. The synthesis system is wider in range of application, compatible with various functional groups, simple in process, convenient in operation, mild in reaction conditions, wider in range of substrates and higher in yield, so that the preparation method is suitable for promotion andapplication.