AbstractPhotodynamic therapy (PDT) has achieved great progress in cancer treatment because it generates reactive oxygen species (ROS) in a noninvasive manner. Nonetheless, the majority of light‐sensitive photosensitizers (PSs) are only sensitive to UV or visible light, suffering limitations such as phototoxicity (UV) and low tissue penetration capabilities (UV–visible). What is more, another impact factor, namely the hypoxic environment within a tumor always inhibits the production of ROS for treatment efficacy. To overcome these problems, herein, one new type‐I PS containing selenium (Se6) is designed. Benefiting from the dual heavy atom effects of selenium and bromine, Se6 can produce short‐lived hydroxyl (•OH) and long‐lived superoxide anion (O2•−) under both normoxic and hypoxic conditions, which is superior to commonly used oxygen‐dependent type‐II PSs, such as chlorine e6, zinc phthalocyanine. Combining Se6 and upconversion nanoparticles with the ability to upconvert near‐infrared (NIR) light to UV–visible light can greatly overcome the tissue penetration depth, phototoxicity, and oxygen‐dependent limitation of the PDT process, which demonstrates a significant performance in vivo to achieve better therapy efficiency.