Photodynamic therapy (PDT) has been extensively used to treat cancer and other malignant diseases because it can offer many unique advantages over other medical treatments such as less invasive, fewer side effects, lower cost, etc. Despite great progress, the efficiency of PDT treatment, as an oxygen-dependent therapy, is still limited by the hypoxic microenvironment in the human tumor region. In this work, we have developed a near-infrared (NIR) activated theranostic nanoplatform based on upconversion nanoparticles (UCNPs), which incorporates PDT photosensitizer (curcumin) and NO donor (Roussin's black salt) in order to overcome hypoxia-associated resistance by reducing cellular respiration with NO presence in the PDT treatment. Our results suggest that the photo-released NO upon NIR illumination can greatly decrease the oxygen consumption rate and hence increase singlet oxygen generation, which ultimately leads to an increased number of cancer cell deaths, especially under hypoxic condition. It is believed that the methodology developed in this study enables to relieve the hypoxia-induced resistance in PDT treatment and also holds great potential for overcoming hypoxia challenges in other oxygen-dependent therapies.