The invention relates to the field of medicine synthesis, in particular to a preparation method of valnemulin hydrochloride, which comprises the following concrete steps: carrying out back flow reaction on pleuromutilin I and paratoluensulfonyl chloride II in basic solvents to obtain sulphonic acid ester III; then, carrying out reaction with 2-sulfydryl-2-methylamphetamine IV under the alkaline condition to obtain thiol ester V; next, carrying out reaction with compound VI under the alkaline condition to obtain crude products of valnemulin VII; and further, preparing the crude products of valnemulin into valnemulin hydrochloride. The method of the invention provides a novel technical path for valnemulin hydrochloride synthesis, and does not need rare metals to be used as catalysts for taking part in reaction, the complicated work procedure is avoided when the reagent consumption is reduced, and the invention ensures the advantages of simplicity, energy saving, low danger and low cost of the industrial production.