Platinum-based photosensitizers are promising anticancer agents in photodynamic therapy. The cytotoxic effects primarily arise from the production of singlet oxygen and platination of DNA. However, their efficacy is limited by drug resistance and hypoxic tumor microenvironment. A naphthalimide-modified cyclometalated platinum(II) complex PtPAN [PA = N-(2-(diethylamino)ethyl)picolinamide, N = N-(2'-ethylhexyl)-4-ethynyl-1,8-naphthalimide] is designed to conquer these problems. PtPAN generates ROS efficiently under both normoxia and hypoxia. It does not interact with DNA and shows low cytotoxicity in the dark, while it kills tumor cells via ROS under near-infrared light irradiation; moreover, it inhibits tumor growth in mice at a low light dose with negligible side effects. PtPAN is the first reported platinum-based photosensitizer that is unreactive to DNA in the dark but highly cytotoxic upon near-infrared (NIR) irradiation for oxygen-independent photodynamic therapy. Owing to its two-photon excitation property (λ = 825 nm), PtPAN may be suitable for the treatment of deep solid tumors.