Prostate cancer is one of the leading causes of death in men worldwide. Photodynamic therapy (PDT) is a new emerging and promising strategy for the treatment of prostate cancer. PDT uses a combination of light and a photosensitizer (PS) to kill cancer cells. However, most photosensitizers (PS) accumulate in normal tissues, in particular the skin and eyes, and can be activated by sunlight, causing severe side effects such as prolonged skin photosensitivity that have limited the clinical application of PDT. Herein, a novel strategy is presented to overcome these limitations using Indocyanine green (ICG) as an activatable PDT agent. We developed a human serum albumin (HSA)-based nanoplatform loaded with Chlorin e6 (Ce6) and ICG. In vitro and in vivo studies showed that ICG effectively turned "OFF" the phototoxicity of Ce6, and the degradation of ICG by laser irradiation at 808 nm turned "ON" the phototoxicity of Ce6. In addition, ICG produced heat upon NIR irradiation to kill cancer cells, which could be used as a photothermal therapy (PTT). Therapeutic efficacy of HSA-ICG-Ce6 NPs in a prostate cancer model showed that tumors were completely damaged in mice treated by combined PTT with activated PDT. Our designed HSA nanoparticles containing ICG and Ce6 could be used as an activatable PDT combined with PTT for the treatment of prostate cancer.