<p>Ischemia–reperfusion (I/R) injury in skin flap transplantation causes acute oxidative damage and inflammation, leading to high failure rates and tissue necrosis. Herein, we present a core–shell Pd@CeO₂ nanozymes that addresses this challenge via a unique electron-injection mechanism across the Pd–CeO₂ interface, conferring unprecedented antioxidant and anti-inflammatory potency. Constructed by confining Pd clusters within a ceria matrix, this nanozyme combines catalase- and superoxide dismutase–like catalytic activities for robust reactive oxygen species (ROS) scavenging. In vitro, Pd@CeO₂ rapidly neutralizes ROS, preventing oxidative cell death by reducing apoptosis and dampening inflammatory signaling, while restoring angiogenic potential. In a rat skin flap I/R model, Pd@CeO₂ significantly improves flap survival and microvascular regeneration while concurrently reducing tissue necrosis, apoptosis, and inflammation, with no observable toxicity. By simultaneously alleviating oxidative stress, cell death, inflammation, and vascular dysfunction, this nanozyme offers a comprehensive therapeutic strategy against I/R injury. This work introduces a new paradigm for nanozyme-based cytoprotection in transplantation, with potential applicability to other ischemic injuries.</p>