The present study aimed to develop a new drug delivery system with efficient drug loading and sustained drug release for potential application in transarterial chemoembolization (TACE). The porous polyvinyl alcohol microspheres (PPVA MS) were prepared by a combination of inverse emulsification and thermal-induced phase separation (TIPS) method, this was followed by the grafting polymerization of sodium 4-styrene sulfonate (SSS) onto the PPVA MS to obtain the grafted PPVA-g-PSSS MS. The prepared PPVA MS showed a well-defined spherical shape with 'honeycomb-like' porous structure, which could be readily tailored by adjusting the quenching temperature. In vitro biocompatibility analysis indicated the non-cytotoxic and hemocompatible nature of PPVA MS. The porous structure and presence of ionically charged groups in the PPVA-g-PSSS MS favoured the loading of cationic doxorubicin (DOX) onto the MS through ionic-interactions and demonstrated a sustained drug release pattern. Moreover, the cytotoxicity of DOX-loaded PPVA-g-PSSS (DOX@PPVA-g-PSSS) MS against HepG2 cells and the intracellular uptake of DOX demonstrated the potent in vitro antitumor activity. Furthermore, the central auricular artery embolization in rabbits showed that both the PPVA-g-PSSS and DOX@PPVA-gPSSS MS could occlude the auricular arteries and induced superior embolization effects, such as progressive ear appearance changes, irreversible parenchymal damage and fibrosis, and ultrastructural alternations in endothelial cells. Besides, the DOX fluorescence was distributed around the embolized arteries, without decreasing its intensity when prolonged embolization up to 15 days. These findings suggest that the newly developed DOX@PPVA-g-PSSS MS could be employed as a promising drug-loaded embolic agent for the treatment of hepatocellular carcinoma.