Photodynamic therapy (PDT) is a non-invasive therapy with many advantages over other therapeutic methods, but it is restricted to treat superficial cancers due to the shallow tissue penetration of visible light. The biological window in the near infrared region (NIR) offers hope to extend the penetration depth, but there is no natural NIR excited photosensitizer. Here, we report a novel photosensitizer: NaYbF4 nanoparticles (NPs). By using a 1,3-diphenylisobenzofuran (DPBF) sensor, we show that the Yb3+ ions can absorb the NIR light and transfer energy directly to oxygen to generate reactive oxygen species (ROS). The efficiency of transferring energy to oxygen by NaYbF4 NPs is comparable to that of traditional photosensitizers. We have carried out PDT both in vitro and in vivo based on NaYbF4 NPs; the results demonstrate that NaYbF4 NPs are indeed an effective NIR photosensitizer, which can help extend the application of PDT to solid tumors owing to the much deeper penetration depth of NIR light.