An intelligentized system that can transport chemotherapeutics to targets in tumors is an attractive strategy to reverse drug resistance in tumor cells. In this work, a doxorubicin (DOX) delivery system composed of PEGylated resveratrol (PEG–GLY–RES) and poly(histidine)–PEG (PEG–PHIS) was prepared, characterized and evaluated for synergistic cancer therapy. RES was chemically linked with PEG as a component and DOX was loaded into the polymeric blends. This system had an average size of 80 nm, and showed the desired pH-dependent drug release properties, with much faster drug release at pH 5.5, mimicking the tumoral microenvironment. The MTT assay showed the drug loaded blends had higher cytotoxicity than free DOX in all doses. Confocal laser scanning microscopy observation and flow cytometry analyses indicated that the blends were efficiently internalized into HeLa cells, released DOX into the cytoplasm, and entered the nuclei. Endocytosis inhibition results proved that the blends entered the HeLa cells mainly through clathrin-mediated endocytosis and macropinocytosis. It has been shown that such co-delivery of RES and DOX is promising for improvement of anti-cancer efficacy.