Photodynamic therapy (PDT) under fluorescence imaging as a selective and non-invasive treatment approach has been widely applied for the therapy of cancer and bacterial infections. However, its treatment efficiency is hampered by high background fluorescence in the first near-infrared window (NIR-I, 700–900 nm) and oxygen-dependent photosensitizing activity of traditional photosensitizers. In this work, we employ gold nanoclusters (BSA@Au) with the second near-infrared (NIR-II, 1000–1700 nm) fluorescence and catalase-like activity as alternative photosensitizers to realize highly efficient PDT. The bright NIR-II fluorescence of BSA@Au enables the visualization of PDT for tumor with a high signal-to-background ratio (SBR = 7.3) in 4T1 tumor-bearing mouse models. Furthermore, the catalase-like activity of BSA@Au endows its oxygen self-supplied capability, contributing to a five-fold increase in the survival period of tumor-bearing mice receiving boosted PDT treatment compared to that of the control group. Moreover, we further demonstrate that BSA@Au-based PDT strategy can be applied to treat bacterial infections. Our studies show the great potential of NIR-II BSA@Au as a novel photosensitizer for boosted PDT against cancer and bacterial infections.