For cancer treatment, collaborative strategies have been the mainstream for overcoming the restrictions resulting from monotherapy. Combining chemotherapy with photodynamic therapy (PDT) has been shown to increase the antitumor effect and reduce side impacts. This study reports a hypoxia-activated prodrug BOD-Azo-single with a PDT agent and aniline mustard connected by the azo bond. With light illumination, BOD-Azo-single exhibited some PDT. Under hypoxic conditions, the azo bond cleaved and released BOD-3-single of higher phototoxicity and aniline mustard of chemotoxicity. In vivo therapeutic experiments showed that BOD-Azo-single with light significantly reduced A375 tumor proliferation with 92% TGI value. Overall, in this study, PDT was employed to address the adverse systemic toxicity of chemotherapy and the released chemotoxicity made up for the inefficiency of PDT in the hypoxic tumor microenvironment, introducing a new strategy for developing combined therapeutic agents to be advantageous to each other. Under a hypoxic tumor environment, BOD-3-single and aniline mustard exerted a strong synergistic effect (CI = 0.25), indicating that BOD-Azo-single is a real bimodal chemo-photodynamic therapeutic agent.