The invention discloses a preparation method of high-purity palonosetron hydrochloride. A synthesis method is as follows: taking 1,2,3,4-tetrahedro-naphthoic acid as a starting raw material, taking quinine as a resolving agent to obtain chiral(S)-1,2,3,4-tetrahedro-naphthoic acid, acylating the chiral(S)-1,2,3,4-tetrahedro-naphthoic acid by using oxalyl chloride, and then reacting with (S)-3-aminoquinuclidine ammonia salt to obtain amide compound; concentrating, adding water to dilute, adding alkali to adjust pH value to obtain (R)-N-((S)-3-quinine)-1,2,3,4-tetralyl-1-formamide; performing reduction reaction on an intermediate under the existence of the sodium borohydride and boron trifluoride diethyl etherate so as to obtain (R)-N-(1-((S)-1,2,3,4-tetralyl)methyl)-3-quinine amine, continuously reacting with the triphosgene and boron trifluoride diethyl etherate, salting, extracting and regulating the pH value to obtain a crude product of the Palonosetron after the reaction is completed; and salting and refining the crude product in isopropanol so as to obtain the Palonosetron Hydrochloride with high purity. The preparation method not only solves the problem that the palonosetron hydrochloride is low in yield and unstable in process for a long time, but also adopts class-three solvent ethyl acetate to extract in the synthesis of each step, the invention is in favor of the environmental protection, and convenient for solvent recycling and cost saving, and is suitable for industrial production.