Photodynamic therapy (PDT) is a minimally invasive treatment that utilizes a photosensitizer, specific light wavelengths, and oxygen to generate reactive oxygen species (ROS), causing oxidative damage and tumor cell death. However, the effectiveness of PDT can be reduced by the intrinsic antioxidant and DNA repair mechanisms of tumor cells. Artemis (SNM1C/DCLRE1C) is an endonuclease essential for repairing DNA double-strand breaks (DSBs) via non-homologous end-joining (NHEJ). Herein, we conducted a high-throughput small-molecule screening and identified Punicalagin (PUG), a natural polyphenol from pomegranate, as a novel Artemis inhibitor with an IC