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Fabrication of PEGylated polymeric prodrug of bufalin (BUF) covalently linked via β-thioester bond increased its water solubility, stability, and in vivo anticancer efficacy.Bufalin (BUF) exhibits promising potential for the treatment of various human cancers. However, its poor water solubility and unsatisfying stability in water limit its further clinical applications. In the current study, we fabricated a novel poly(ethylene glycol) (PEG)-based polymeric prodrug of BUF, PEGS-BUF, to improve its water solubility and stability at the prerequisite of maintaining its original anticancer activity. Water soluble and biocompatible PEG was firstly reacted with maleic anhydride (MAH) to afford carboxyl-terminated PEG, PEG-MAH. Then the double bond was reacted with n-propyl mercaptan via the Michael addition reaction to afford PEGS-COOH. At last, the 3α-hydroxyl group of BUF was reacted with the terminal carboxyl group of PEGS-COOH via esterification reaction to afford the final polymeric prodrug, PEGS-BUF, endowing BUF good water solubility, stability, and anticancer activity. It was demonstrated that the water solubility and stability of PEGS-BUF improved dramatically compared with that of its small molecular counterpart, BUF. Besides, both in vitro and in vivo experiments showed that PEGS-BUF exhibited comparable anticancer activity in comparison with that of free BUF.