Hypoxia has a major role in tumor development and resistance to therapy. Therefore, the effective targeting and killing of hypoxic tumor cells is a key to successful tumor control. Here, we report the hypoxia-responsive prodrug micelles to deliver hydrophobic anticancer drug, which can selectively release the drugs to treat hypoxic tumor cells in a combined way. For this purpose, an azobenzene (AZO) bond, which imparts hypoxia sensitivity and specificity as cross linker, conjugated PEG-hexanethiol (PEG-C6) with combretastatin A-4 (CA4) to form PEG-C6-AZO-CA4 amphiphilicmolecule. These PEG-C6-AZO-CA4 molecules self-assemble into micelles, which can encapsulate hydrophobic anticancer drug. The drug release behavior from PEG-C6-AZO-CA4 micelles was studied under normoxic or hypoxic conditions and the combinations of CA4 with hydrophobic drugs for tumor treatment in vitro were also investigated. As the first example of using AZO linkages to develop anticancer prodrug micelles as hydrophobic anticancer drugs delivery to kill the hypoxic tumor cells in a combination way, this study establishes PEG-C6-AZO-CA4 micelles as a promising drug delivery platform for hypoxic tumor therapy.