mPEGylated artesunate prodrug was synthesized via esterification between poly(ethylene glycol) monomethyl ether (mPEG) and artesunate (ART). The product was inclined to form nanocapsules in aqueous media due to its amphiphilic nature. These nanocapsules showed narrow size distribution, with an average particle size of 88.7 nm measured by dynamic laser scattering (DLS). Their vesical morphology was further confirmed by transmission electron microscopy (TEM). We found that the release of ART from the nanocapsules was controllable, which was contributed to the easily hydrolyzed property of the ester bond. In addition, the cytotoxicity of the prodrug against L1210 and MCF7 cell lines showed an essential decrease compared with the free ART. These results present a new strategy in designing anti-tumor ART nanocapsules for targeting tumor cells.