Recently, photodynamic therapy (PDT), one of the phototherapy methods, requires various therapeutic strategies to overcome the limitations of photosensitizer (PS) with hydrophobicity and non-selectivity. In this study, we designed a reactive oxygen species (ROS)-degradable hydrogel [e.g., full name 필요 (PNIPAM-C/PS)] based on a thermo-sensitive polymer (poly(N-isopropylacrylamide)) containing PS for effective localized PDT of cancer. We successfully synthesized a crosslinker with a thioketal bond degradable by ROS, and a thermo-sensitive injectable hydrogel was fabricated using the ROS-responsive crosslinker. PNIPAM-based injectable hydrogel was able to be injected through syringe needles at room temperature, but it was converted to gel phase through phase transition at 37 °C above full name 필요 (LCST). PNIPAM-C/PS injectable hydrogel prepared using ROS-degradable crosslinker was selectively degraded in ROS environments and showed good biocompatibility before and after degradation. When irradiated with a 670 nm laser, PNIPAM-C/PS injectable hydrogel showed high phototoxicity by ROS generation. The PNIPAM-C/PS injectable hydrogel with selective degradation properties and excellent phototoxicity by ROS could be promising materials for effective localized PDT of cancer.