The invention provides a preparation method of deuterated entecavir. The preparation method comprises the following steps: mixing commercially available entecavir, a deuteration reagent and an alkaline reagent; stirring and reacting at -40 DEG C to 150 DEG C for 1 to 72h; after finishing reaction, crystallizing and filtering; washing with water and washing with the deuteration reagent in sequence;removing a solvent; decompressing and drying to obtain a deuterated entecavir crude product; refining the deuterated entecavir crude product to obtain the deuterated entecavir shown as the followingformula; the formula is shown in the description. The preparation method is simple, simple and convenient to operate, low in cost and easy for purification. The commercially available entecavir is subjected to alkali addition reaction in a deuteration solvent atmosphere and is simply treated to obtain a pure product. The entecavir is marked by deuterium so that a metabolic process and pharmacodynamics of the entecavir in a human body is easily comprehensively analyzed and the entecavir has a better pharmaceutical effect and a smaller side effect.