Hypoxia in most solid tumors is a major challenge for photodynamic therapy (PDT), and the combination of hypoxia-activated chemotherapy and PDT is a promising approach for enhanced anticancer activity. Herein, we designed hypoxia-responsive polymeric nanoprodrug PNPs to co-deliver photosensitizer 5,10,5,20-tetrakis(4-aminophenyl)-porphine (TAPP) and chlorambucil (CB) to improve the overall therapeutic efficacy. Upon laser irradiation, the central TAPP converted oxygen to produce single oxygen (O) for PDT and induced PDT-reduced hypoxia environment, which accelerated the release of activated CB for synergetic cancer cell killing. Consequently, these hypoxia-responsive polymeric nanoprodrugs with a considerable drug-loading content and synergistic therapeutic effect of PDT-CT had great potential for tumor therapy.