This review explores the role of damage-associated molecular patterns (DAMPs) in radiation injury and their potential as therapeutic targets. Ionizing radiation exposure leads to acute radiation syndrome (ARS), characterized by hematopoietic, gastrointestinal, and neurovascular damage. Radiation-induced DNA damage and oxidative stress trigger various forms of cell death, including apoptosis, necrosis, and ferroptosis. DAMPs, released by injured or dying cells, activate pattern recognition receptors, triggering inflammatory responses that exacerbate tissue and organ damage. In ARS, infection and sepsis further increase DAMP release, worsening outcomes. DAMPs such as eCIRP, HMGB1, mtDNA, and exRNA are involved in the pathogenesis of radiation injury. The release of DAMPs can occur through passive or active pathways, including apoptosis, necrosis, pyroptosis, and ferroptosis. DAMPs are also released via exosomes and lysosomal exocytosis. Targeting DAMPs offers potential therapeutic strategies to mitigate radiation injury. Current research focuses on developing inhibitors of DAMP signaling, such as monoclonal antibodies, decoy receptors, and small molecules, to reduce inflammation and improve survival in radiation injury. The review highlights the importance of understanding DAMP mechanisms in radiation injury to develop effective countermeasures against radiation-related diseases and accidents.This review explores the role of damage-associated molecular patterns (DAMPs) in radiation injury and their potential as therapeutic targets. Ionizing radiation exposure leads to acute radiation syndrome (ARS), characterized by hematopoietic, gastrointestinal, and neurovascular damage. Radiation-induced DNA damage and oxidative stress trigger various forms of cell death, including apoptosis, necrosis, and ferroptosis. DAMPs, released by injured or dying cells, activate pattern recognition receptors, triggering inflammatory responses that exacerbate tissue and organ damage. In ARS, infection and sepsis further increase DAMP release, worsening outcomes. DAMPs such as eCIRP, HMGB1, mtDNA, and exRNA are involved in the pathogenesis of radiation injury. The release of DAMPs can occur through passive or active pathways, including apoptosis, necrosis, pyroptosis, and ferroptosis. DAMPs are also released via exosomes and lysosomal exocytosis. Targeting DAMPs offers potential therapeutic strategies to mitigate radiation injury. Current research focuses on developing inhibitors of DAMP signaling, such as monoclonal antibodies, decoy receptors, and small molecules, to reduce inflammation and improve survival in radiation injury. The review highlights the importance of understanding DAMP mechanisms in radiation injury to develop effective countermeasures against radiation-related diseases and accidents.