PEGylated superoxide dismutase (PEG-SOD) is commonly used as a cytoprotective agent in radiotherapy. However, its effectiveness in preventing radiation dermatitis is limited owing to its poor skin permeability. To address this issue, a PEG-SOD-loaded dissolving microneedle (PSMN) patch was developed to effectively prevent radiation dermatitis. Initially, PSMN patches were fabricated using a template mold method with polyvinylpyrrolidone K90 as the matrix material. PSMNs exhibited a conical shape with adequate mechanical strength to penetrate the stratum corneum. More than 90 % of PEG-SOD was released from the PSMN patches within 30 min. Notably, the PSMN patches showed a significantly higher drug skin permeation than the PEG-SOD solutions, with a 500-fold increase. In silico simulations and experiments on skin pharmacokinetics confirmed that PSMN patches enhanced drug permeation and skin absorption, in contrast to PEG-SOD solutions. More importantly, PSMN patches efficiently mitigated ionizing radiation-induced skin damage, accelerated the healing process of radiation-affected skin tissues, and exhibited highly effective radioprotective activity for DNA in the skin tissue. Therefore, PSMN patches are promising topical remedy for the prevention of radiation dermatitis.