An active-targeting and smart pH-sensitive nanoparticle drug delivery system with high drug loading was developed by conjugating doxorubicin (DOX) to xyloglucan (XG) through acid-cleavable hydrazone bonds, and then encapsulating DOX by the self-assembly of xyloglucan–doxorubicin conjugates (XG–DOX) to ensure a sufficient amount of drug delivered in the tumor region. The galactose moiety of XG, as an ideal targeting moiety, could be recognized and internalized by asialoglycoprotein receptor (ASGP-R), which is especially ample in hepatocytes. And then the abundant DOX of xyloglucan–doxorubicin nanoparticle drug delivery systems (DOX nano-DDSs) could be highly accumulated and released in drug resistant tumor cells to exert maximum therapeutic effects. Compared with free DOX, the novel DOX nano-DDSs apparently showed longer circulation time, larger intracellular uptake, more drug release, higher cytotoxicity against drug resistant HepG2 (HepG2/DOX) cells and greater effects for inhibiting the growth of the tumor volume and decreasing systemic toxicity. Even though there was no significant enhancement in intracellular uptake and cytotoxicity between the DOX nano-DDSs and XG–DOX, the loading content of DOX of DOX nano-DDSs reached 23%, which is higher than that of XG–DOX conjugates. Moreover, the DOX nano-DDSs obviously presented better anti-tumor effects in in vivo assays. In conclusion, these novel DOX nano-DDSs exhibited remarkable anti-tumor effects and few side effects, which is significantly promising for the clinical therapy of cancer.