Ferroptosis, a novel form of nonapoptotic cell death, can effectively enhance photodynamic therapy (PDT) performance by disrupting intracellular redox homeostasis and promoting apoptosis. However, the extremely hypoxic tumor microenvironment (TME) together with highly expressed hypoxia-inducible factor-1α (HIF-1α) presents a considerable challenge for clinical PDT against osteosarcoma (OS). Hence, an innovative nanoplatform that enhances antitumor PDT by inducing ferroptosis and alleviating hypoxia is fabricated. Capsaicin (CAP) is widely reported to specifically activate transient receptor potential vanilloid 1 (TRPV1) channel, trigger an increase in intracellular Ca concentration, which is closely linked with ferroptosis, and participate in decreased oxygen consumption by inhibiting HIF-1α in tumor cells, potentiating PDT antitumor efficiency. Thus, CAP and the photosensitizer IR780 are coencapsulated into highly biocompatible human serum albumin (HSA) to construct a nanoplatform (CI@HSA NPs) for synergistic tumor treatment under near-infrared (NIR) irradiation. Furthermore, the potential underlying signaling pathways of the combination therapy are investigated. CI@HSA NPs achieve real-time dynamic distribution monitoring and exhibit excellent antitumor efficacy with superior biosafety in vivo. Overall, this work highlights a promising NIR imaging-guided "pro-death" strategy to overcome the limitations of PDT for OS by promoting ferroptosis and alleviating hypoxia, providing inspiration and support for future innovative tumor therapy approaches.