The drug-based hyperbranched polymers have attracted broad interest from scientists as for their attractive and distinctive characteristics in cancer chemotherapy. However, the only use of single-drug treatment modality could lead to low or unsatisfactory anticancer activity becuase of the limited treatment strategy and multidrug resistance of tumour cells. In this work, a novel dual drug-based hyperbranched polymer (DHBP) simultaneously containing methotrexate (MTX) and chlorambucil (Cb) was proposed to realize synergistic cancer chemotherapy. After modification by PEG, the obtained DHBP-g-PEG self-assembled into hyperbranched polymer micelles (HBPMs) in aqueous solution with a high drug loading capacity and stable drug transport. Notably, HBPMs with excellent controlled drug release in tumour cells exhibited an obviously superior synergistic effect and possessed significant therapeutic efficiency in vitro anticancer activity, as compared to either individual drug or mixture drugs treatment group. All these results demonstrate that the unique advantage of HBPMs may hold significant potential application in the field of synergistic cancer chemotherapy.